Ferroptosis as a potential new therapeutic target for diabetes and its complications

in Endocrine Connections
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Qian Deng Graduate College of Anhui University of Chinese Medicine, Hefei, China

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Yue Zhu Graduate College of Anhui University of Chinese Medicine, Hefei, China

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Mengmeng Zhang Graduate College of Anhui University of Chinese Medicine, Hefei, China

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Aihua Fei Department of Endocrinology, The Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China

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Jiaqi Liang Graduate College of Anhui University of Chinese Medicine, Hefei, China

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Jinjin Zheng Graduate College of Anhui University of Chinese Medicine, Hefei, China

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Qingping Zhang College of Acupuncture-moxibustion and Tuina, Anhui University of Chinese Medicine, Hefei, China

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Tong Cheng Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China

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Xia Ge Department of Endocrinology, The Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China

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https://orcid.org/0000-0002-8630-718X

Correspondence should be addressed to X Ge or Q Zhang or T Cheng: xiage@ahtcm.edu.cn or zqp202202@163.com or chengtong.ct@163.com

*(Q Deng and Y Zhu contributed equally to this work)

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Diabetes is a complex metabolic disease. In recent years, diabetes and its chronic complications have become a health hotspot of global concern. It is very important to find promising therapeutic targets and directions. Ferroptosis is a new type of programmed cell death that is different from cell necrosis, apoptosis, and autophagy. Ferroptosis is mainly characterized by iron-dependent lipid peroxidation. With the reduction of the anti-oxidative capacity of cells, the accumulated reactive lipid oxygen species will cause oxidative cell death and lead to ferroptosis at lethal levels. Recent studies have shown that ferroptosis plays an important regulatory role in the initiation and development of diabetes, as well as various complications of diabetes. In this review, we will summarize new findings related to ferroptosis and diabetic complications and propose ferroptosis as a potential target for treating diabetic complications.

Abstract

Diabetes is a complex metabolic disease. In recent years, diabetes and its chronic complications have become a health hotspot of global concern. It is very important to find promising therapeutic targets and directions. Ferroptosis is a new type of programmed cell death that is different from cell necrosis, apoptosis, and autophagy. Ferroptosis is mainly characterized by iron-dependent lipid peroxidation. With the reduction of the anti-oxidative capacity of cells, the accumulated reactive lipid oxygen species will cause oxidative cell death and lead to ferroptosis at lethal levels. Recent studies have shown that ferroptosis plays an important regulatory role in the initiation and development of diabetes, as well as various complications of diabetes. In this review, we will summarize new findings related to ferroptosis and diabetic complications and propose ferroptosis as a potential target for treating diabetic complications.

Introduction

Diabetes is a metabolic disorder which was characterized by hyperglycemia (1), and the prevalence of diabetes and prediabetes in adults around the world has increased in recent decades. Based on the statistic from the International Diabetes Federation, the number of adults with diabetes in the world will reach 537 million in 2021, compared with 2019, the number increased by 16%. Moreover, the adult population with diabetes in the world will reach 783 million by 2045 (2). Persistent hyperglycemia of diabetes is the basis of its chronic complications, multiple organs are involved in it, such as the kidneys, retina, bones and joints, nervous system (peripheral, central), cardiovascular system, etc. (3). Diabetes greatly affects the patient’s health and life quality. Oral hypoglycemic agents and exogenous insulin supplementation are commonly used in the treatment of diabetes, but these treatments only provide temporary glycemic control and cannot prevent effectively the occurrence of diabetic complications. Therefore, more research is urgently needed to explore and discover effective treatment strategies for diabetes and its complications.

As a hot topic, ferroptosis was focused on by many people over the past few years. Ferroptosis was a programmed cell death mode that is unlike other cell death modes (4). In 2003, Brent R Stockwell's research group at the Whitehead Institute of Biomedical Research investigated the mechanism of small molecule Erastin-induced death of tumor cells with RAS mutation using high-throughput screening of anticancer drugs (5). The study found that this type of cell death was significantly different from other types of cell death at the biochemical, morphological, and genetic levels. This new type of cell death caused by the accumulation of ferrous ions (Fe2+)-dependent lipid peroxides was named ferroptosis in 2012 (4). With the in-depth explorations of new biological molecules involved in the ferroptosis process, the regulatory mechanism of ferroptosis has become more and more complex. Studies indicated that ferroptosis was significantly regulated by pharmacological perturbations of lipid repair systems, including glutathione (GSH), and glutathione peroxidase (GPX4), additionally, ferroptosis was also dependent on a group of active enzymic reactions, such as the biosynthesis of phospholipids (PL) containing polyunsaturated fatty acids, and the selective oxygenation of polyunsaturated fatty acid-phosphatidylethanolamine by lipoxygenase (6, 7, 8).

Moreover, the metabolisms of iron and glucose are closely associated with each other. According to the existing studies, the metabolism of glucose was tightly affected by the deficiency or excess of iron (9), conversely, high glucose (HG) can lead to iron overload, which in turn induces ferroptosis. The main pathological manifestations of diabetes are peripheral insulin resistance and pancreatic islet beta cell failure. The death or dysfunction of pancreatic islet β-cells leads to an absolute or relative insufficient secretion of insulin, which increases blood sugar and leads to diabetes. The studies in pancreatic islet beta cells and proximal renal tubular epithelial cells showed that HG was a causative factor for ferroptosis (10, 11, 12). Hyperglycemia leads to the overproduction of reactive oxygen species (ROS) and subsequently enhances oxidative stress. The increased HG and lipid ROS production, which were closely associated with pancreatic islet beta cell death, are enabling factors for ferroptosis in the diabetic microenvironment (13). Due to the massive production of endogenous ROS and the low expression of antioxidant enzymes, pancreatic islet beta cells are highly susceptible to oxidative stress and prone to ferroptosis. One study showed that the ferroptosis inducer Erastin could significantly reduce the secretion of insulin from pancreatic islet beta cells, while this impaired insulin secretion was significantly rescued by the administration of the ferroptosis inhibitor Ferrostatin-1 (Fer-1) (14). The pieces of evidence earlier suggest that ferroptosis has participated in the processes of pancreatic islet beta cell death and its dysfunction. Furthermore, as an antioxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) was also significantly associated with the onset and outcome of ferroptosis (13), meanwhile, many ferroptosis-associated molecules, such as the molecules involved in GSH, GPX4, iron (ferritin, transferrin, heme oxygenase), and lipid metabolism, are tightly regulated by Nrf2 (15). The enhanced ferroptosis was observed in the cells with inactivated, inhibited, and deficient Nrf2. Studies have shown that impaired activation of Nrf2 was significantly associated with the ferroptosis of islet β cells (13). GPX4 is an anti-lipoperoxidase, a key regulator of ferroptosis, it can reduce complex hydroperoxides to their corresponding counterparts and lipid hydroperoxides (LOOH) to lipid alcohol (LOH), thus interrupting the lipid peroxidation chain reaction (16). The high expression of GPX4 in those insulin-producing cell lines and primary islet cells was observed recently; moreover, depletion of GPX4 also leads to dramatically low cell viability (17). These observations demonstrated that the activation of the Nrf2/GPX4 axis could protect β cells from ferroptosis. Collectively, the occurrence and development of diabetes may be tightly associated with ferroptosis.

Overview of ferroptosis

Ferroptosis is an iron-dependent, nonapoptotic form of cell death. Specifically, it is a result of an imbalance between intracellular lipid ROS generation and degradation. Ferroptosis will be caused when the ROS is accumulated and the antioxidant capacity of cells decreases. Distinct from the features of necrosis, autophagy, and apoptosis, ferroptosis could result in compromised plasma membrane integrity, mild chromatin condensation, cytoplasm and cytoplasmic organelles swelling, increased mitochondrial membrane density, and decreased or absent mitochondrial cristae eventually (4). According to existing studies, many extrinsic or intrinsic pathways could trigger the initiation of ferroptosis. Although more relevant mechanisms of ferroptosis remain unidentified, many biological processes, such as iron metabolism, lipid metabolism, GSH metabolism, mevalonate pathway, NADPH (nicotinamide adenine dinucleotide phosphate)-FSP1 (ferroptosis inhibitory protein 1)-coenzyme Q10 (CoQ10) (18), have significantly participated in the occurrence and execution of ferroptosis. Additionally, deficiency of cysteine and inhibition of GSH synthesis contribute to ferroptosis, and CoQ10 and its reduced form CoQ10-H2, NADPH levels, selenium, and Nrf2 expression are also tightly associated with ferroptosis. Moreover, ferroptosis can be induced by any of these pathways’ impairment. Herein, the underlying mechanisms of ferroptosis will be discussed (Fig. 1).

Figure 1
Figure 1

Three mechanisms of ferroptosis. The regulation mechanism of ferroptosis is mainly related to the regulation of iron metabolism, lipid metabolism, and glutathione metabolism. (ACSL4, acyl-CoA synthetase long-chain family member 4; CP, ceruloplasmin; DMT1, divalent 311 metal transporter 1; FPN, ferroportin; GCL, glutamate cysteine ligase; GPX4, glutathione peroxidase 4; GSH, glutathione; GSS, glutathione synthetase; GSSG, glutathione oxidized; HP, hephaestin; LOX, lipoxygenase; LPCAT3, lysophosphatidylcholine acyltransferase 3; NADPH, nicotinamide adenine dinucleotide phosphate; PL-OOH, phospholipid hydroperoxides; PUFA, polyunsaturated fatty acids; PUFA-CoA, polyunsaturated fatty acyl CoA; PUFA-PL, phospholipid-bound polyunsaturated fatty acids; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; STEAP3, the six-transmembrane epithelial antigen of the prostate 3; TF, transferrin; TFR1, transferrin receptor1).

Citation: Endocrine Connections 12, 3; 10.1530/EC-22-0419

Iron metabolism

Having a redox property, iron can directly participate in the diffusion of lipid peroxidation and the formation of free radicals. The level of ferritin in the body is directly related to ferroptosis, and iron plays a crucial role in ferroptosis (4). Circulating iron binds to transferrin (Tf) in the form of ferric iron (Fe3+). After introduction into cells via membrane protein transferrin receptor 1 (TfR1), Fe3+ is localized to endosomes. In endosomes, due to the acidic environment of endosomes, Fe3+ is released from Tf and reduced to ferrous iron (Fe2+) by the ferrireductase activity of the six-transmembrane epithelial antigen of the prostate 3. Then, under the regulation of divalent metal transporter 1 (DMT1, also known as SLC11A2), the Fe2+ is released from endosomes into the labile iron pool in the cytoplasm, where it is stored in 24 light chains of ferritin (FTL) and 24 heavy chains of ferritin (FTH). Alternatively, through the Fenton reaction, Fe2+ and hydrogen peroxide can catalyze the formation of hydroxyl radicals (OH) (19), increase the level of intracellular ROS, and lead to lipid peroxidation. Conversely, excess Fe2+ is exported through Ferroportin (FPN), the only known iron-exporting protein, and oxidized to Fe3+ by ferroxidase or ceruloplasmin, and then combined with Tf, and finally re-entered into the circulation. A dysfunctional iron homeostasis plays a critical role in ferroptosis.

Lipid metabolism

Except for iron, lipid peroxidation and impaired lipid metabolism are other two triggers of ferroptosis (20). Additionally, existing evidence also showed that polyunsaturated fatty acids (PUFA) also play a key role in ferroptosis (21). The studies using Lipidomic analysis revealed that ferroptosis selectively preferentially oxidizes PUFA-containing PL, especially phosphatidylethanolamine (PE) containing arachidonic acid or epinephrine arachidonic acid in the plasma membrane (6, 22). Acyl-coenzyme A (CoA) synthase long-chain family member 4 (ACSL4) is a key enzyme in regulating lipid composition and is significantly involved in PUFA-PE biosynthesis and remodeling in cells. In lipid metabolism pathways, free cytoplasmic PUFAs are bound to CoA by ACSL4, and then PUFA-CoA is incorporated into PL in the plasma membrane by lysophosphatidylcholine acyltransferase 3. Lipoxygenase (Lox) is a nonheme-containing dioxygenase that can catalyze PUFA through its specific peroxidation and may also be an important regulator of ferroptosis. 12/15Lox oxidation of PUFA-PL causes PL hydroperoxide to accumulate on the plasma membrane (23), eventually leading to iron death.

Glutathione metabolism

Under physiological conditions, cells fight against lipid peroxidation using GPX4. As a necessary selenium protein, lipid peroxides (LOOH) could be converted into non-toxic lipids by GPX4 to resist iron- and oxygen-dependent lipid peroxidation (24). GPX4 is the only member of the GPX4 family that can reduce lipid peroxides (LOOH) and plays a significant regulatory role in ferroptosis (25). Furthermore, RSL3-induced cell death was prevented by GPX4 overexpression (26). GSH is a cofactor of GPX4 and is synthesized from glutamate, glycine, and cysteine. The biosynthesis of GSH requires the uptake of cystine through the cystine/glutamate antiporter (system Xc-). GPX4 reduces safely PL hydroperoxides to the corresponding lipid alcohols using two GSH molecules, producing HO and glutathione disulfide as byproducts. Inhibition of the Xc-system results in reduced cystine uptake, cysteine depletion, and a lack of synthetic substrates for GSH, which in turn impairs the function of GPX4 (27), leading to homeostatic imbalance. Additionally, the depletion of GPX4 leads to an increase in intracellular iron, which results in PL hydroperoxide accumulation, thereby disrupting membrane integrity through the ferroptosis pathway.

Ferroptosis in diabetic complications

The discovery of ferroptosis has become a hot topic of research and many new areas of disease progression were revealed in recent years, such as cardiovascular diseases, cancer, neurodegenerative diseases, metabolic diseases, ischemia–reperfusion injury (IRI), and damage to the liver, kidneys, and many more (Fig. 2). Recently, a large number of studies have documented the vital impact of ferroptosis on the development of diabetic complications. Later, we will discuss in detail the key molecular mechanisms of ferroptosis in diabetic complications (Fig. 3).

Figure 2
Figure 2

Ferroptosis plays an important role in heart disease, liver disease, gastrointestinal disease, lung disease, kidney disease, pancreatic disease, retinal disease, brain system disease, and other systemic diseases.

Citation: Endocrine Connections 12, 3; 10.1530/EC-22-0419

Figure 3
Figure 3

Genes involved in the regulation of ferroptosis in diabetes and diabetic complications.

Citation: Endocrine Connections 12, 3; 10.1530/EC-22-0419

Diabetic nephropathy

Diabetic nephropathy (DN) is one of the serious microvascular complications of diabetes and the leading cause of end-stage renal disease worldwide (28). Regardless of glycemic control, all diabetic patients will potentially develop DN (29, 30, 31). According to a previous study, DN was potentially associated with ferroptosis (32). Since renal tubules are prone to metabolic disturbance and ischemia, tubular defects may be an important cause of proteinuria in patients with DN (33). Because of the high sensitivity of the renal tubules to lipid peroxidation and oxidative stress (34), frequently occurred ferroptosis of renal tubules was observed in the development of renal disease (35). Meanwhile, ferroptosis-caused tubular damage was also found in patients with diabetes. In comparison to the non-treated control renal tubular cells, the cells with transforming growth factor beta-1 (TGFB1) stimulation exhibited significantly decreased intracellular GSH production and elevated lipid peroxidation. In addition, compared to the normal control samples collected from healthy controls, the renal biopsy samples collected from diabetic patients showed dramatically reduced mRNA expression of the cystine/glutamate antiporter system Xc− (xCT) and GPX4, suggesting the occurrence of ferroptosis (10). Ferroptosis is triggered by the accumulation of lipid peroxide through mechanisms dependent on xCT and GPX4. Meanwhile, the TGFB1-induced ferroptosis could be significantly suppressed by ferroptosis inhibitors in renal tubular cells. Moreover, renal fibrosis can be induced by diabetic tubular cell death and ferroptosis. A previous study reported that increased activation of pro-inflammatory and profibrotic signaling pathways was observed in the renal tubular epithelial cells under HG conditions (36). The results from in vivo experiments have shown that ferroptosis promotes diabetic renal tubular injury in db/db mice through the hypoxia-inducible factor (HIF)-1α/heme oxygenase (HO)-1 pathway (32). The ferroptosis-inducing regulator GPX4 induces acute renal failure in mice when it is inactivated (27). As we know, HG-induced glomerular podocyte injury was considered one of the primary mechanisms of DN. As an antioxidant enzyme, peroxiredoxin 6 (PRDX6) could negatively regulate the development of ferroptosis. Previous research has demonstrated that the protective effect of PRDX6 is significantly abolished by the treatment of ferroptosis inducer erastin, suggesting the suppressive effect of PRDX6 on ferroptosis and its protective effect on the HG-induced podocyte injury (37). Significant changes in some ferroptosis-associated biomarkers, such as increased ACSL4 expression, decreased GPX4 expression, and elevated content of lipid peroxide and iron, were observed in the kidney of the mouse with DN. The ACSL4 inhibitor rosiglitazone can significantly reduce lipid peroxide malondialdehyde and iron content, inhibit inflammation in DN, and thus impair ferroptosis (38). These studies suggest that ferroptosis plays a significant role in the occurrence and development of DN. However, in addition to the reported and explored ferroptosis-related mechanisms, whether there are more regulatory pathways that mediate the occurrence and development of ferroptosis is unclear. We should conduct more studies on the specific mechanisms of ferroptosis to expand our understanding and treatment of DN.

Diabetic retinopathy

Diabetic retinopathy (DR) is the most common microvascular complication in people with diabetes and can cause blindness in severe cases (39), and hyperglycemia is a major risk element for DR. Iron overload leads to increased intracellular iron deposition, which in turn leads to irreversible tissue damage and organ failure (40). Ferroptosis is also considered as a programmed cell death which is highly dependent on iron. The increased iron accumulation which was found in the retina of a diabetic mouse model and significantly affects the integrity of the blood–retinal barrier (BRB) and accelerates the damage of retinal cells through enhanced oxidative stress (41). Retinal pigment epithelium cells (RPEs) are located between photoreceptor cells and the choroid of the eye (42). The disruption of the BRB caused by the damage of RPE cells is also significantly associated with DR (43). There are high levels of ROS in RPE cells; however, in normal circumstances, the antioxidant system will remove excess ROS. The alternation of antioxidant system activity which is mainly caused by hyperglycemia increased the RPE cells’ production of ROS in DR, which is considered as the major reason for the loss of RPE cell function. A previous experiment in vitro showed that HG can increase the death of RPE cells by promoting ferroptosis (44). Additionally, the down-regulated Nrf2 expression was observed in RPE cells, and the cell damage caused by HG can be efficiently inhibited through the activation of Nrf2 in DR (45). There is evidence that the ferroptosis inhibitors Fer-1 and deferoxamine could rescue RPE cells from death more effectively than the inhibitors of necroptosis and apoptosis (46). Taken together, ferroptosis plays a major role in the death of RPE cells. Ferroptosis may become a new target for the treatment of DR. However, whether ferroptosis is involved in HG-induced death of other retinal neurons needs further research to prove.

Diabetic osteoporosis

Diabetic osteoporosis (DOP) is considered as one of the serious complications of diabetes. Epidemiological surveys have shown that (47) approximately 50–66% of patients will be complicated with osteopenia, and approximately 33% of patients will develop osteoporosis among diabetic patients. DOP is the main cause of fragility fractures and trabecular deterioration in diabetic patients (48). The diabetic microenvironment significantly enhances the ferroptosis of osteocyte ferroptosis in vitro, and thus, loss of osteocyte activity is considered as one of the key pathogenic factors of DOP (49). Through activation of abnormal HO1, a cell-inducible oxidative stress regulator (50), in vitro and in vivo, ferroptosis mediates the death of bone cells and the pathogenesis of DOP in mouse models of DOP. In addition, the usage of ferroptosis inhibitor Fer-1 could effectively rescue the death of osteocytes in DOP (51). The presence of iron overload has been linked with osteoporosis and caused bone loss (52). In a previous study, it was found that the levels of circulating ferritin and serum iron were significantly increased in DOP rats compared to those in normal rats. Meanwhile, the results of immunohistochemistry showed that the expression of solute carrier family 7 member 11 (SLC7A11) and GPX4, two of the main inhibitory proteins of ferroptosis, was significantly decreased, suggesting the existence of ferroptosis in bone tissue of rats with diabetic bone loss. Furthermore, studies have shown that (53, 54) HG could induce ferroptosis in type 2 DOP, through increasing ROS, lipid peroxidation, and depletion of GSH, more importantly, melatonin strengthens bone microstructure, inhibits osteoblast ferroptosis, and enhances the osteogenic capacity of MC3T3-E1 cells in vivo and in vitro by activating Nrf2/HO1 signaling pathways (11). Ferroptosis plays a role in HG-induced DOP through activating the METTL3/ASK1-p38 (methyltransferase-like3/apoptosis signal-regulating kinase 1-p38) signaling pathway, and HG-induced osteoblast ferroptosis may be the major cause of DOP (55). However, more detailed mechanisms still require further study.

Diabetic cerebrovascular disease

Diabetic cerebrovascular disease (DCD) refers to cerebrovascular disease induced by diabetes, which mainly includes intracranial microvascular disease and macrovascular disease. Stroke is a major macrovascular complication of DCD, and hyperglycemia could significantly increase the risk of stroke (56). Vascular lumen stenosis caused by large intracranial atherosclerosis is one of the most common causes of stroke, and the formation of atherosclerotic plaques (AS) is associated with a hypercoagulable state. The incidence of AS is obviously increased by insulin resistance in patients with T2DM. The main feature of DCD is the imbalance of vascular homeostasis caused by the dysfunction of smooth muscle cells and endothelial, which ultimately leads to AS thrombosis (57). Studies have shown that ferroptosis was the main form of endothelial death in atherosclerotic vascular cell death, and the deficiency of heme oxygenase 1 (HMOX1) could significantly attenuate Fe overloading, decrease iron content and ROS level, and subsequently reduce lipid peroxidation, which in turn resulted in reduced ferroptosis in endothelial cells of diabetic patients (58). Recent evidence suggested that ferroptosis may occur during the development and progression of AS, and inhibition of ferroptosis may significantly impair the deterioration of thoracic aortic AS by reducing lipid peroxidation and endothelial dysfunction (59). The Nrf2-Keap1 pathway could reduce AS-related ferroptosis by maintaining cellular iron homeostasis and increasing GSH, NADPH, and GPX4. P53 plays different roles in the ferroptosis of AS at different stages in transcription-dependent and transcription-independent ways (60). Although ferroptosis plays an important role in the occurrence of AS, its relationship with DCD still requires more direct evidence to be proved.

Diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM) is a major complication and the main cause of death in T2DM patients (61) and is characterized by left ventricular hypertrophy, increased myocardial stiffness, impaired diastolic function, and increased myocardial fibrosis and systolic dysfunction (62). It can be caused by hyperlipidemia, hyperglycemia, over-nourishment, age, heredity, and the environment, among other factors (63). Due to the imbalance of the antioxidant system and the production of excessive ROS, cardiomyocytes will undergo ferroptosis, apoptosis, inflammation, and fibrosis. Palmitic acid (PA), the most common saturated long-chain fatty acid in food, can induce myocardial damage and is considered a key factor of obesity and T2DM-related cardiomyopathy development (64, 65). A recently published study showed that the ferroptosis inhibitor Fer-1 could induce PA-caused hepatocyte death (66). Heat shock factor 1 (HSF1) is a stress-responsive transcription factor that plays a dominant role in the heat shock response (67). HSF1 is induced in various cardiovascular diseases (68) and can protect cardiomyocytes from IRI (69). Accumulated evidence suggested that HSF1 may be involved in the regulation of ferroptosis (70, 71, 72). An interesting experiment demonstrated that ferroptosis was associated with PA-induced cardiomyocyte death, and HSF1 exerted a significant cardioprotective effect on PA-induced cardiomyocyte death by inhibiting ferroptosis (73). The incidence of myocardial ischemia in diabetic patients is 2.45–2.99 times that of non-diabetic patients (74), and cardiomyocyte IRI is more likely to occur in diabetic patients. This increases oxidative stress caused by hyperglycemia and excessive ROS production to some extent (75). Diabetic myocardial IRI is closely associated with endoplasmic reticulum (ER) stress and ROS production (76), and ER stress plays an important role in ferroptosis by inducing unfolded protein response (77). A previous experiment has shown that ferroptosis is associated with the pathological process of diabetic myocardial IRI through the pathway related to ER stress, and inhibition of ferroptosis can alleviate diabetic myocardial IRI (78). However, this experiment only initially confirmed the effect of ferroptosis on ER stress and cardiomyocyte injury, and more research is needed to prove it. Iron homeostasis is critical for the development of cellular ferroptosis (4), and ferroportin 1 (FPN1) plays an important role in iron homeostasis and is the only protein associated with iron release. Nrf2 is a key regulator of antioxidant responses, activating the Nrf2-related pathway could obviously improve the myocardial oxidative damage and cell death, which in turn can alleviate myocardial IRI in Type 1 diabetes (T1DM) patients (79). Additionally, regulation of Nrf2 expression could efficiently protect cardiomyocytes from ferroptosis (80). Due to the controlling of FPN1 transcription by Nrf2, activating the Nrf2/FPN1 pathway can significantly reduce myocardial IRI by regulating ferroptosis and iron homeostasis (81). Fe2+ overload is a culprit in cardiomyocyte ferroptosis and heart failure, demonstrating that iron levels are critical for cardiac homeostasis (82). Endothelial dysfunction is a hallmark of diabetes, meanwhile, endothelial dysfunction is also considered as key and initiating factor in the pathogenesis of cardiovascular complications in diabetes (83). Ferroptosis is found to be related to endothelial dysfunction, and activation of the p53–xCT–GSH axis plays a crucial role in the ferroptosis of endothelial cells and endothelial dysfunction (84). Several emerging compounds can be used today to target key ferroptosis regulators to alleviate diabetic myocardial dysfunction. For example, exogenous spermine could attenuate DCM, alleviate oxidative stress, reduce fibrosis, and upregulate myocardial CaSR by blocking the Nrf2–ROS–p53–MuRF1 axis in a diabetic rat model (85). Obeticholic acid can modulate farnesoid X receptor/Nrf2 signaling to inhibit cardiac inflammatory factors and attenuate DCM (86). However, it remains to be investigated whether the protective effects of these compounds are associated with ferroptosis in diabetic cardiomyocytes. At present, most of the evidence on the involvement of ferroptosis in the progress of DCM comes from in vitro studies, and there are relatively few studies on real animal models and clinical studies, so more research evidence is needed to prove the relevance of targeting ferroptosis in the treatment of DCM.

Influence of ferroptosis inhibition on diabetic complications

Iron, as a trace element, is necessary for the human body; however, excessive iron could lead to serious damage to the human body, because the abnormal accumulation of iron will generate a large number of free radicals, resulting in damage to DNA, proteins, or other biomolecules (87). Although iron overload has a negative effect on the initiation and progression of DN, the intrinsic mechanism of injury has not been clearly explained. Studies have shown that low-iron diets or iron chelators delay the progression of DN in diabetic rats (88, 89), which provides a new explanation for the pathogenesis of iron overload in this disease. Fer-1, an inhibitor of ferroptosis, can protect multiple organs and tissues from ischemic injury in mouse models and also has protective effects in models of diabetes. Additionally, through activating the PI3K-AKT signaling pathway, Fer-1-mediated inhibition of ferroptosis could significantly reduce inflammation, promote proliferation and migration of vascular endothelial cells and epithelial cells, and improve wound healing (8).

Astragaloside IV (AS-IV) (C41H68O14) is a high-purity natural product extracted from Astragalus membranaceus and has a wide range of pharmacological effects, such as anti-inflammation, antioxidation, immune response enhancement, and anti-stress (90). AS-IV has been shown to inhibit the death of RPE cells during STZ-induced DR by increasing the expression of miR-128, while also inhibiting HG-induced cell damage (91). The latest evidence showed that AS-IV could restore silent information regulator 2-related enzyme 1/Nrf2 activity and the expression of antioxidant-related molecules by inhibiting miR-138-5P expression, thus reducing ferroptosis and inhibiting HG-induced death of RPE cells, suggesting the regulatory function of AS-IV on the RPE cells by ferroptosis suppression and potential therapeutic value of AS-IV for DR treatment (92). Platycodin D (PD) is a triterpenoid saponin with multiple pharmacological properties and has diverse pharmacologic activities, including anti-allergic, anti-inflammatory, and antitumor activities (93). Studies have shown that PD can up-regulate the expression of GPX4 to inhibit HG-induced ferroptosis in HK-2 cells, suggesting that PD may be helpful in the treatment of DN, but more clinical studies are needed to prove it (94). Glabridin is the main ingredient in licorice root, which is often used to improve metabolic abnormalities (such as obesity and diabetes) and has anti-cancer, anti-inflammatory, and other effects (95). Tan et al.'s research showed that GLAB can improve DN in rats, which may be achieved by inhibiting ferroptosis and regulating VEGF/Akt/ERK pathways (96). Resveratrol (RSV) is a natural polyphenol with antioxidant, anti-inflammatory, anti-cancer, anti-aging, anti-diabetic, and protective functions for the heart and nerves (97). A previous study showed that low doses of RSV can reduce blood sugar levels and improve insulin sensitivity in diabetic patients (98). In addition, the protection of low doses of RSV on the acrolein-induced ferroptosis and insulin secretion dysfunction in MIN6 cells through the ER stress-related PERK (Phospho-ERK) signaling pathway was also observed in a published study (99). Sulforaphane, an activator of Nrf2, has been shown to prevent diabetes-induced oxidative stress and cardiac dysfunction (100), and experiments have shown that SFN can inhibit cardiomyocyte ferroptosis in the heart of DCM mice by activating Nrf2, upregulating the levels of ferritin and SLC7A11, and improving DCM in mice (101). Umbelliferone (7-hydroxycoumarin; UMB) is a compound of coumarin, which has antibacterial, antioxidative, antihyperglycemic, and other activities (102), UMB can inhibit HG-induced ferroptosis and oxidative stress by activating the Nrf2/HO1 pathway, thereby preventing renal tubular cell damage and having a protective effect on DN (103). The abovementioned compounds are summarized in Table 1.

Table 1

Compounds that interfere with ferroptosis to affect diabetes complications.

Compounds Function Possible role in ferroptosis Reference
Fer-1 Inhibition of TGFβ1 stimulated changes in GSH levels and lipid peroxidation in cultured renal tubular cells, which in turn inhibited ferroptosis. Inhibitor (10)
Exogenous spermine Block Nrf2-ROS-p53-MuRF1 axis to attenuate DCM. Inhibitor (85)
Quercetin Certain therapeutic effects on T2DM by inhibiting islet iron deposition and islet β-cell ferroptosis. Inhibitor (105)
Astragaloside IV Modulates RPE cell function by inhibiting the expression of miR-138-5P, which in turn inhibits ferroptosis. Inhibitor (99)
Platycodin D Inhibits ferroptosis through up-regulating the expression of GPX4 in HK-2 cells. Inhibitor (101)
Resveratrol Inhibits acrolein-induced ferroptosis in MIN6 cells. Inhibitor (102)
Sulforaphane Transduction of the NRF2-metallothionein pathway via AMPK/Akt/GSK-3β signaling. Inhibitor (103)
Umbelliferone Inhibits ferroptosis through activation of the Nrf-2/HO-1 pathway to delay the progression of diabetic nephropathy. Inhibitor (108)
Allopurinol Facilitate Nrf2/p62 signaling to attenuate DCM Inhibitor (106)
Germacrone Promotes the treatment of DN by inactivating ferroptosis-dependent mitochondrial damage and podocyte apoptosis. Inhibitor (107)
Cryptochlorogenic Inhibits ferroptosis in diabetic patients by activating cystine/xCT/GPX4/Nrf2 and inhibiting NCOA4. Inhibitor (12)
Glabridin Inhibits ferroptosis through regulating VEGF/Akt/ERK pathways in DN. Inhibitor (103)

There are many drugs that have entered the clinic that can also inhibit the occurrence of ferroptosis, thereby producing a certain effect on diabetic complications. Fenofibrate is mostly used to treat hypertriglyceridemia (104). Numerous studies have shown that fenofibrate can improve diabetic complications, but this effect is not dependent on its lipid-lowering ability (105, 106, 107). Studies have shown that by up-regulating Nrf2 expression, fenofibrate treatment also changed the expression of GPX4, SLC7A11, FTH1, TFR1, and other markers related to ferroptosis, which can inhibit diabetes-related ferroptosis, thus delaying the progression of DN (108, 109, 110). Canagliflozin (Cana) is a new sodium-glucose cotransporter 2 inhibitor (SGLT2i) hypoglycemic drug; it can improve diabetic myocardial structure and function, preserve cardiac microvascular barrier function and integrity, sustain eNOS phosphorylation and endothelium-dependent relaxation, as well as improve microvessel density and perfusion (111), and may also reduce the risk of cardiovascular events in people with type 2 diabetes (112). However, the potential mechanism of CANA treatment of DCM still needs to be further explored. Studies have shown that CANA may inhibit ferroptosis by stabilizing cardiac iron steady and inhibiting myocardial oxidative stress, thereby achieving the effect of treating DCM (113). Therefore, CANA may be used as an adjunct to insulin therapy in the process of preventing and treating DCM. N-acetylcysteine (NAC) is an antioxidant that has been used as a drug for nearly 60 years. More and more evidence shows that NAC has a good therapeutic effect in reducing diabetic microvascular complications (114), and NAC is expected to be a drug candidate for the treatment of DN (115). NAC improves ferroptosis by activating the expression of GPX4 through the SITR3-SOD2 pathway, and NAC combined with insulin therapy can effectively improve DN by inhibiting ferroptosis and maintaining mitochondrial redox homeostasis, which suggests that NAC may be used as an adjuvant drug in the treatment of DN (116). Liraglutide is a widely used clinical glucagon-like peptide-1 receptor inhibitor that can be used to treat obesity and diabetes (117). There is evidence that liraglutide can reduce db/db mouse plays a crucial role in ferroptosis in db/db mice (118). Liraglutide attenuates damage to hippocampal neurons and synaptic plasticity and restores cognitive function by inhibiting hippocampal iron death in diabetic cognitive impairment mice (119). All of these compounds and drugs have properties that inhibit ferroptosis; however, their exact targets remain to be further validated.

Conclusions

Ferroptosis, a novel mode of cell death, is characterized by the accumulation of iron-dependent lipid peroxides and lethal ROS. More and more studies have been conducted on ferroptosis in recent years, but research on ferroptosis still faces challenges, because its exact mechanism is still being explored and related theories also need further investigations. This article reviewed the three basic regulatory pathways of ferroptosis and the participation of ferroptosis in the development of diabetes and its complications through various pathways, such as the iron metabolism pathway, GPX4, Nrf2, cystine/glutamate antiporter system, Nrf2/FPN1, HIF-1α/HO-1, and so on. Some studies have shown that activating Nrf2 can effectively inhibit the occurrence of ferroptosis, thereby saving cell death and treating diseases, but other studies prevent the emergence of ferroptosis by inhibiting the activation of Nrf2, so we speculate that, whether Nrf2 acts differently on cells under different conditions needs more experiments to prove. Complications of diabetes can affect almost every organ in the body, so it is necessary to continuously explore more effective methods for treatment and therapy. Iron chelators and other ferroptosis inhibitors have shown a good regulatory effect in animal and cell experiments related to diabetes and its complications. The emergence of many natural products and drugs also provides new ideas and new therapeutic targets for the treatment of diabetes and its complications. However, there is growing evidence of crosstalk between ferroptosis and other types of cell death, and it is critical to selectively label ferroptosis-associated cells; therefore, it is necessary to further elucidate this interrelationship in the future, which is a prerequisite for exploring ferroptosis-related mechanisms. At present, many studies are focused on animals or at the molecular level. It is necessary to further improve the research on the pathogenesis of ferroptosis, clarify the specific biomarkers for ferroptosis in clinical research, look for in vivo indicators, and conduct more clinical research as appropriate. The therapeutic effect of ferroptosis inhibitors in diabetic complications also requires further randomized clinical trials to verify. At the same time, finding the marker protein of ferroptosis can also provide new opportunities for subsequent disease diagnosis and therapeutic intervention.

Declaration of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

This study was supported by Natural Science Foundation of Anhui Province Youth Project (2008085QH391) and Technology talents Youth Project of Anhui University of Chinese Medicine (2021qnyc09).

Author contribution statement

Writing—original draft preparation, Qian Deng and Yue Zhu; writing—search previous information, Mengmeng Zhang, Aihua Fei, Jiaqi Liang, and Jinjin Zheng; writing—review and editing, Xia Ge, Tong Cheng, Qingping Zhang. All authors agree to be accountable for the content of the work.

Acknowledgments

We thank professor Hang Song for revising this review.

References

  • 1

    Jürgen H, & Michael R. Diabetes mellitus–definition, Klassifikation, diagnose, screening und Prävention (update 2019). Wiener Klinische Wochenschrift 2019 131 615. (https://doi.org/10.1007/s00508-019-1450-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, Stein C, Basit A, Chan JCN & Mbanya JC et al.IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Research and Clinical Practice 2022 183 109119. (https://doi.org/10.1016/j.diabres.2021.109119)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Deshpande AD, Harris-Hayes M, Schootman M. Epidemiology of diabetes and diabetes-related complications. Physical Therapy 2008 88 12541264. (https://doi.org/10.2522/ptj.20080020)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM & Yang WS et al.Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012 149 10601072. (https://doi.org/10.1016/j.cell.2012.03.042)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Sonam D, Stephen LL, William CH, & Brent RS. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 2003 3 285296. (https://doi.org/10.1016/s1535-6108(0300050-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Scott JD, Georg EW, Leila SM, Eric DL, Berend S, Manuele R, Giulio S, & Brent RS. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chemical Biology 2015 10 16041609. (https://doi.org/10.1021/acschembio.5b00245)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, Irmler M, Beckers J, Aichler M & Walch A et al.ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nature Chemical Biology 2017 13 9198. (https://doi.org/10.1038/nchembio.2239)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Brent RS, José Pedro Friedmann A, Hülya B, Ashley IB, Marcus C, Scott JD, Simone F, Sergio G, Stavroula KH, & Valerian EK. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017 171 273285. (https://doi.org/10.1016/j.cell.2017.09.021)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Fillebeen C, Lam NH, Chow S, Botta A, Sweeney G, Pantopoulos K. Regulatory connections between iron and glucose metabolism. International Journal of Molecular Sciences 2020 21 7773. (https://doi.org/10.3390/ijms21207773)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Seonghun K, Shin-Wook K, Jeongho J, Seung Hyeok H, Huiyoon S, Bo Young N, Jimin P, Tae-Hyun Y, Gyuri K, & Pureunchowon L. Characterization of ferroptosis in kidney tubular cell death under diabetic conditions. Cell Death and Disease 2021 12 160. (https://doi.org/10.1038/s41419-021-03452-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Hongdong M, Xindong W, Weilin Z, Haitian L, Wei Z, Jun S, &Maowei Y. Melatonin suppresses ferroptosis induced by high glucose via activation of the Nrf2/HO-1 signaling pathway in type 2 diabetic osteoporosis. Oxidative Medicine and Cellular Longevity 2020 2020 1–1 8. (https://doi.org/10.1155/2020/9067610)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Zhou Y The protective effects of cryptochlorogenic acid on β-cells function in diabetes in vivo and vitro via inhibition of ferroptosis. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2020 13 1921–1931. (https://doi.org/10.2147/DMSO.S249382)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Ana S, Tamara S, Milica M, Milica V, Ilijana G, Vesna M, Dragica G, Andjelija I, Ksenija V, & Nevena S. Ferroptosis as a novel determinant of β-cell death in diabetic conditions. Oxidative Medicine and Cellular Longevity 2022 2022 1–19. (https://doi.org/10.1155/2022/3873420)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Antonio B, Andrew RP, Rena LP, Boris G, Anissa FG, Tatsuya K, Karen S, Gregory SK, Stefan RB, &Andreas L. Ferroptosis-inducing agents compromise in vitro human islet viability and function. Cell Death and Disease 2018 9 595. (https://doi.org/10.1038/s41419-018-0506-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Kerins MJ, Ooi A. The roles of NRF2 in modulating cellular iron homeostasis. Antioxidants and Redox Signaling 2018 29 17561773. (https://doi.org/10.1089/ars.2017.7176)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Seibt TM, Proneth B, Conrad M. Role of GPX4 in ferroptosis and its pharmacological implication. Free Radical Biology and Medicine 2019 133 144152. (https://doi.org/10.1016/j.freeradbiomed.2018.09.014)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Bastian K, Thomas P, Anne J, Sigurd L, &Ilir M. The central role of glutathione peroxidase 4 in the regulation of ferroptosis and its implications for pro-inflammatory cytokine-mediated beta-cell death. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 2021 1867 166114. (https://doi.org/10.1016/j.bbadis.2021.166114)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Kenichi S, Rachid S, Anna K, Wan Seok Y, Miki H, Scott JD, Lewis MB, Carlos AV, Adam JW, &Brent RS. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nature Chemical Biology 2016 497503. (https://doi.org/10.1038/nchembio.2079)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Dimitrios G, Alexandra B, &Kostas P. Iron homeostasis and oxidative stress: an intimate relationship. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 2019 1866 118535. (https://doi.org/10.1016/j.bbamcr.2019.118535)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Stockwell BR, Jiang X. The chemistry and biology of ferroptosis. Cell Chemical Biology 2020 27 365375. (https://doi.org/10.1016/j.chembiol.2020.03.013)

  • 21

    Wan Seok Y, Katherine JK, Michael MG, Milesh P, Mikhail SS, &Brent RS. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. PNAS 2016 113 E4966E4975. (https://doi.org/10.1073/pnas.1603244113)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Valerian EK, Gaowei M, Feng Q, Jose Pedro Friedmann A, Sebastian D, Claudette St C, Haider Hussain D, Bing L, Vladimir AT, & Vladimir BR. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nature Chemical Biology 2017 13 8190. (https://doi.org/10.1038/nchembio.2238)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Anthonymuthu TS, Kenny EM, Shrivastava I, Tyurina YY, Hier ZE, Ting HC, Dar HH, Tyurin VA, Nesterova A & Amoscato AA et al.Empowerment of 15-lipoxygenase catalytic competence in selective oxidation of membrane ETE-PE to ferroptotic death signals, HpETE-PE. Journal of the American Chemical Society 2018 140 1783517839. (https://doi.org/10.1021/jacs.8b09913)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Ursini F, Maiorino M, Gregolin C. The selenoenzyme phospholipid hydroperoxide glutathione peroxidase. Biochimica et Biophysica Acta 1985 839 6270. (https://doi.org/10.1016/0304-4165(8590182-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, Roveri A, Peng X, Porto Freitas F & Seibt T et al.Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 2018 172 409422.e21. (https://doi.org/10.1016/j.cell.2017.11.048)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Xinbing S, Ruonan Z, Shuiping L, Ting D, Lijuan Z, Mingming Z, Xuemeng H, Yu X, Xingxing H, &Haoming L. RSL3 drives ferroptosis through GPX4 inactivation and ROS production in colorectal cancer. Frontiers in Pharmacology 2018 9 1371. (https://doi.org/10.3389/fphar.2018.01371)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A & Eggenhofer E et al.Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature Cell Biology 2014 16 11801191. (https://doi.org/10.1038/ncb3064)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z & Shahinfar S et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. New England Journal of Medicine 2001 345 861869. (https://doi.org/10.1056/NEJMoa011161)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Sanchez-Niño MD, Benito-Martin A, Ortiz A. New paradigms in cell death in human diabetic nephropathy. Kidney International 2010 78 737744. (https://doi.org/10.1038/ki.2010.270)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Elmarakby AA, Sullivan JC. Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovascular Therapeutics 2012 30 4959. (https://doi.org/10.1111/j.1755-5922.2010.00218.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Guha M, Xu ZG, Tung D, Lanting L, Natarajan R. Specific down‐regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes. FASEB Journal 2007 21 33553368. (https://doi.org/10.1096/fj.06-6713com)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Xiaomeng F, Shuo W, Zhencheng S, Hengbei D, Haitian Y, Mengxiu H, & Xia G. Ferroptosis enhanced diabetic renal tubular injury via HIF-1α/HO-1 pathway in db/db mice. Frontiers in Endocrinology 2021 21 12. (https://doi.org/10.3389/fendo.2021.626390)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Sydney CWT, Joseph CKL, &Kar Neng L. Diabetic tubulopathy: an emerging entity. Diabetes and the Kidney 2011 170 124134. (https://doi.org/10.1159/000325647)

  • 34

    Ratliff BB, Abdulmahdi W, Pawar R, Wolin MS. Oxidant mechanisms in renal injury and disease. Antioxidants and Redox Signaling 2016 25 119146. (https://doi.org/10.1089/ars.2016.6665)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Deng F, Sharma I, Dai Y, Yang M, Kanwar YS. myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule. Journal of Clinical Investigation 2019 129 50335049. (https://doi.org/10.1172/JCI129903)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Nath KA Tubulointerstitial changes as a major determinant in the progression of renal damage. American Journal of Kidney Diseases 1992 20 117. (https://doi.org/10.1016/s0272-6386(1280312-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Zhang Q, Hu Y, Hu JE, Ding Y, Shen Y, Xu H, Chen H, Wu N. Sp1-mediated upregulation of Prdx6 expression prevents podocyte injury in diabetic nephropathy via mitigation of oxidative stress and ferroptosis. Life Sciences 2021 278 119529. (https://doi.org/10.1016/j.lfs.2021.119529)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Wang Y, Bi R, Quan F, Cao Q, Lin Y, Yue C, Cui X, Yang H, Gao X, Zhang D. Ferroptosis involves in renal tubular cell death in diabetic nephropathy. European Journal of Pharmacology 2020 888 173574. (https://doi.org/10.1016/j.ejphar.2020.173574)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Lynch SK, Abràmoff MD. Diabetic retinopathy is a neurodegenerative disorder. Vision Research 2017 139 101107. (https://doi.org/10.1016/j.visres.2017.03.003)

  • 40

    Powell LW, Seckington RC, Deugnier Y. Haemochromatosis. Lancet 2016 388 706716. (https://doi.org/10.1016/S0140-6736(1501315-X)

  • 41

    Kapil C, Wanwisa P, Sudha A, Rajalakshmi V, Amany T, Pachiappan A, Pamela M, Sylvia BS, Muthusamy T, & Oleg K. Iron overload accelerates the progression of diabetic retinopathy in association with increased retinal renin expression. Scientific Reports 2018 8 3025. (https://doi.org/10.1038/s41598-018-21276-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Xia T, Rizzolo LJ. Effects of diabetic retinopathy on the barrier functions of the retinal pigment epithelium. Vision Research 2017 139 7281. (https://doi.org/10.1016/j.visres.2017.02.006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Rafael S, Marta V, Lídia C, Cristina H, &Marta G. The retinal pigment epithelium: something more than a constituent of the blood-retinal barrier—implications for the pathogenesis of diabetic retinopathy. Journal of Biomedicine and Biotechnology 2010 2010 115. (https://doi.org/10.1155/2010/190724)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Meng-Yu W, Giou-Teng Y, Tzu-Ting L, &Chia-Jung L. The oxidative stress and mitochondrial dysfunction during the pathogenesis of diabetic retinopathy. Oxidative Medicine and Cellular Longevity 2018 2018 115. (https://doi.org/10.1155/2018/3420187)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Zhang J, He J. CTRP3 inhibits high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells. Artificial Cells, Nanomedicine, and Biotechnology 2019 47 37583764. (https://doi.org/10.1080/21691401.2019.1666864)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Totsuka K, Ueta T, Uchida T, Roggia MF, Nakagawa S, Vavvas DG, Honjo M, Aihara M. Oxidative stress induces ferroptotic cell death in retinal pigment epithelial cells. Experimental Eye Research 2019 181 316324. (https://doi.org/10.1016/j.exer.2018.08.019)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Sahar M, MYH MM, AlDarmaki RS, Tekes K, Kalász H, Adeghate EA. An update on therapies for the treatment of diabetes-induced osteoporosis. Expert Opinion on Biological Therapy 2019 19 937948. (https://doi.org/10.1080/14712598.2019.1618266)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Napoli N, Chandran M, Pierroz DD, Abrahamsen B, Schwartz AV, Ferrari SL & IOF Bone and Diabetes Working Group. Mechanisms of diabetes mellitus-induced bone fragility. Nature Reviews. Endocrinology 2017 13 208219. (https://doi.org/10.1038/nrendo.2016.153)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Vikram VS, Stinus H, Morten F, Kim B, &Anne PH. Bone disease in diabetes: another manifestation of microvascular disease? Lancet Diabetes & Endocrinology 2017 827838. (https://doi.org/10.1016/S2213-8587(1730134-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cellular and Molecular Life Sciences 2016 73 32213247. (https://doi.org/10.1007/s00018-016-2223-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Yiqi Y, Yixuan L, Minqi W, Kai Y, Qishan W, Pei M, Jingke D, Zhifeng Y, Shengbing Y, &Kai H. Targeting ferroptosis suppresses osteocyte glucolipotoxicity and alleviates diabetic osteoporosis. Bone Research 2022 10 26. (https://doi.org/10.1038/s41413-022-00198-w)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Jaime T, Zheiwei Y, & Patrick F, Susanna C, Hong F, Rhima C, Philipp M, Stephen BD, Robert WG, & Patricia JG. Bone loss caused by iron overload in a murine model: importance of oxidative stress. Blood, the Journal of the American Society of Hematology 2010 116 25822589. (https://doi.org/10.1182/blood-2009-12-260083)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53

    Zhai Z, Chen W, Hu Q, Wang X, Zhao Q, Tuerxunyiming M. High glucose inhibits osteogenic differentiation of bone marrow mesenchymal stem cells via regulating miR-493-5p/ZEB2 signalling. Journal of Biochemistry 2020 167 613621. (https://doi.org/10.1093/jb/mvaa011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    Wang X, Ma H, Sun J, Zheng T, Zhao P, Li H, Yang M. Mitochondrial ferritin deficiency promotes osteoblastic ferroptosis via mitophagy in type 2 diabetic osteoporosis. Biological Trace Element Research 2022 200 298307. (https://doi.org/10.1007/s12011-021-02627-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55

    Lin Y, Shen X, Ke Y, Lan C, Chen X, Liang B, Zhang Y, Yan S. Activation of osteoblast ferroptosis via the METTL3/ASK1‐p38 signaling pathway in high glucose and high fat (HGHF)‐induced diabetic bone loss. FASEB Journal 2022 36 e22147. (https://doi.org/10.1096/fj.202101610R)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    Chen R, Ovbiagele B, Feng W. Diabetes and stroke: epidemiology, pathophysiology, pharmaceuticals and outcomes. American Journal of the Medical Sciences 2016 351 380386. (https://doi.org/10.1016/j.amjms.2016.01.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57

    Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. European Heart Journal 2013 34 24362443. (https://doi.org/10.1093/eurheartj/eht149)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    Meng Z, Liang H, Zhao J, Gao J, Liu C, Ma X, Liu J, Liang B, Jiao X & Cao J et al.HMOX1 upregulation promotes ferroptosis in diabetic atherosclerosis. Life Sciences 2021 284 119935. (https://doi.org/10.1016/j.lfs.2021.119935)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59

    Bai T, Li M, Liu Y, Qiao Z, Wang Z. Inhibition of ferroptosis alleviates atherosclerosis through attenuating lipid peroxidation and endothelial dysfunction in mouse aortic endothelial cell. Free Radical Biology and Medicine 2020 160 92102. (https://doi.org/10.1016/j.freeradbiomed.2020.07.026)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60

    Yuqin W, Yajie Z, Ting Y, Liming Y, Yanna S, & Hong L. Ferroptosis signaling and regulators in atherosclerosis. Frontiers in Cell and Developmental Biology 2021 9 809457. (https://doi.org/10.3389/fcell.2021.809457)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61

    Tan Y, Zhang Z, Zheng C, Wintergerst KA, Keller BB, Cai L. Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence. Nature Reviews. Cardiology 2020 17 585607. (https://doi.org/10.1038/s41569-020-0339-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62

    Paolillo S, Marsico F, Prastaro M, Renga F, Esposito L, De Martino F, Di Napoli P, Esposito I, Ambrosio A & Ianniruberto M et al.Diabetic cardiomyopathy: definition, diagnosis, and therapeutic implications. Heart Failure Clinics 2019 15 341347. (https://doi.org/10.1016/j.hfc.2019.02.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63

    Zhou H, Wang S, Zhu P, Hu S, Chen Y, Ren J. Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biology 2018 15 335346. (https://doi.org/10.1016/j.redox.2017.12.019)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64

    Zhu H, Tan Y, Du W, Li Y, Toan S, Mui D, Tian F, Zhou H. Phosphoglycerate mutase 5 exacerbates cardiac ischemia-reperfusion injury through disrupting mitochondrial quality control. Redox Biology 2021 38 101777. (https://doi.org/10.1016/j.redox.2020.101777)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65

    Zhou H, Ren J, Toan S, Mui D. Role of mitochondrial quality surveillance in myocardial infarction: from bench to bedside. Ageing Research Reviews 2021 66 101250. (https://doi.org/10.1016/j.arr.2020.101250)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66

    Qi J, Kim JW, Zhou Z, Lim CW, Kim B. Ferroptosis affects the progression of nonalcoholic steatohepatitis via the modulation of lipid peroxidation–mediated cell death in mice. American Journal of Pathology 2020 190 6881. (https://doi.org/10.1016/j.ajpath.2019.09.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67

    Vydra N, Toma A, Widlak W. Pleiotropic role of HSF1 in neoplastic transformation. Current Cancer Drug Targets 2014 14 144155. (https://doi.org/10.2174/1568009614666140122155942)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 68

    Gray CC, Amrani M, Yacoub MH. Heat stress proteins and myocardial protection: experimental model or potential clinical tool? International Journal of Biochemistry and Cell Biology 1999 31 559573. (https://doi.org/10.1016/s1357-2725(9900004-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69

    Zou Y, Zhu W, Sakamoto M, Qin Y, Akazawa H, Toko H, Mizukami M, Takeda N, Minamino T & Takano H et al.Heat shock transcription factor 1 protects cardiomyocytes from ischemia/reperfusion injury. Circulation 2003 108 30243030. (https://doi.org/10.1161/01.CIR.0000101923.54751.77)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70

    Ma X, Xu L, Alberobello AT, Gavrilova O, Bagattin A, Skarulis M, Liu J, Finkel T, Mueller E. Celastrol protects against obesity and metabolic dysfunction through activation of a HSF1-PGC1α transcriptional axis. Cell Metabolism 2015 22 695708. (https://doi.org/10.1016/j.cmet.2015.08.005)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71

    Sun X, Ou Z, Xie M, Kang R, Fan Y, Niu X, Wang H, Cao L, Tang D. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene 2015 34 56175625. (https://doi.org/10.1038/onc.2015.32)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72

    Yan LJ, Christians ES, Liu L, Xiao X, Sohal RS, Benjamin IJ. Mouse heat shock transcription factor 1 deficiency alters cardiac redox homeostasis and increases mitochondrial oxidative damage. EMBO Journal 2002 21 51645172. (https://doi.org/10.1093/emboj/cdf528)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 73

    Wang N, Ma H, Li J, Meng C, Zou J, Wang H, Liu K, Liu M, Xiao X & Zhang H et al.HSF1 functions as a key defender against palmitic acid-induced ferroptosis in cardiomyocytes. Journal of Molecular and Cellular Cardiology 2021 150 6576. (https://doi.org/10.1016/j.yjmcc.2020.10.010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 74

    Ndumele CE, Matsushita K, Lazo M, Bello N, Blumenthal RS, Gerstenblith G, Nambi V, Ballantyne CM, Solomon SD & Selvin E et al.Obesity and subtypes of incident cardiovascular disease. Journal of the American Heart Association 2016 5 e003921. (https://doi.org/10.1161/JAHA.116.003921)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 75

    Romesh K, &Diep DN. Glucose control and cardiovascular outcomes: reorienting approach. Frontiers in Endocrinology 2012 3 110. (https://doi.org/10.3389/fendo.2012.00110)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 76

    Runkel ED, Liu S, Baumeister R, Schulze E. Surveillance-activated defenses block the ROS–induced mitochondrial unfolded protein response. PLOS Genetics 2013 9 e1003346. (https://doi.org/10.1371/journal.pgen.1003346)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 77

    Lee YS, Lee DH, Choudry HA, Bartlett DL, Lee YJ. Ferroptosis-induced endoplasmic reticulum stress: cross-talk between ferroptosis and apoptosis. Molecular Cancer Research 2018 16 10731076. (https://doi.org/10.1158/1541-7786.MCR-18-0055)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 78

    Li W, Li W, Leng Y, Xiong Y, Xia Z. Ferroptosis is involved in diabetes myocardial ischemia/reperfusion injury through endoplasmic reticulum stress. DNA and Cell Biology 2020 39 210225. (https://doi.org/10.1089/dna.2019.5097)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 79

    Bin Z, Mengen Z, Buying L, Zhenhua L, Kaifeng L, Liqing J, Meng Z, Wei Y, Jian Y, &Dinghua Y. Honokiol ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by reducing oxidative stress and apoptosis through activating the SIRT1-Nrf2 signaling pathway. Oxidative Medicine and Cellular Longevity 2018 2018 116. (https://doi.org/10.1155/2018/3159801)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 80

    La Rosa P, Petrillo S, Turchi R, Berardinelli F, Schirinzi T, Vasco G, Lettieri-Barbato D, Fiorenza MT, Bertini ES & Aquilano K et al.The Nrf2 induction prevents ferroptosis in Friedreich's ataxia. Redox Biology 2021 38 101791. (https://doi.org/10.1016/j.redox.2020.101791)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 81

    Tian H, Xiong Y, Zhang Y, Leng Y, Tao J, Li L, Qiu Z, Xia Z. Activation of NRF2/FPN1 pathway attenuates myocardial ischemia–reperfusion injury in diabetic rats by regulating iron homeostasis and ferroptosis. Cell Stress and Chaperones 2022 27 149164. (https://doi.org/10.1007/s12192-022-01257-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 82

    Alosaimi B, Hamed ME, Naeem A, Alsharef AA, AlQahtani SY, AlDosari KM, Alamri AA, Al-Eisa K, Khojah T & Assiri AM et al.MERS-CoV infection is associated with downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated inflammatory innate immune response in the lower respiratory tract. Cytokine 2020 126 154895. (https://doi.org/10.1016/j.cyto.2019.154895)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 83

    Widlansky ME, Gokce N, Keaney JF, Vita JA. The clinical implications of endothelial dysfunction. Journal of the American College of Cardiology 2003 42 11491160. (https://doi.org/10.1016/s0735-1097(0300994-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 84

    Er-Fei L, Hong-Xia L, Yu-Han Q, Yong Q, Gao-Liang Y, Yu-Yu Y, Lin-Qing L, Jian-Tong H, Cheng-Chun T, & Dong W. Role of ferroptosis in the process of diabetes-induced endothelial dysfunction. World Journal of Diabetes 2021 12 124–1 37. (https://doi.org/10.4239/wjd.v12.i2.124)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 85

    Wang Y, Chen J, Li S, Zhang X, Guo Z, Hu J, Shao X, Song N, Zhao Y & Li H et al.Exogenous spermine attenuates rat diabetic cardiomyopathy via suppressing ROS-p53 mediated downregulation of calcium-sensitive receptor. Redox Biology 2020 32 101514. (https://doi.org/10.1016/j.redox.2020.101514)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 86

    Wu H, Liu G, He Y, Da J, Xie B. Obeticholic acid protects against diabetic cardiomyopathy by activation of FXR/Nrf2 signaling in db/db mice. European Journal of Pharmacology 2019 858 172393. (https://doi.org/10.1016/j.ejphar.2019.05.022)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 87

    Zager RA Parenteral iron compounds: potent oxidants but mainstays of anemia management in chronic renal disease. Clinical Journal of the American Society of Nephrology 2006 1(Supplement 1) S24S31. (https://doi.org/10.2215/CJN.01410406)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 88

    Remuzzi A, Puntorieri S, Brugnetti B, Bertani T, Remuzzi G. Renoprotective effect of low iron diet and its consequence on glomerular hemodynamics. Kidney International 1991 39 647652. (https://doi.org/10.1038/ki.1991.77)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 89

    Nath KA, Fischereder M, Hostetter TH. The role of oxidants in progressive renal injury. Kidney International. Supplement 1994 45 S111S115.

  • 90

    Yang L, Han X, Yuan J, Xing F, Hu Z, Huang F, Wu H, Shi H, Zhang T, Wu X. Early astragaloside IV administration attenuates experimental autoimmune encephalomyelitis in mice by suppressing the maturation and function of dendritic cells. Life Sciences 2020 249 117448. (https://doi.org/10.1016/j.lfs.2020.117448)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 91

    Wang T, Zhang Z, Song C, Sun L, Sui X, Qu Q, Liu J. Astragaloside IV protects retinal pigment epithelial cells from apoptosis by upregulating miR128 expression in diabetic rats. International Journal of Molecular Medicine 2020 46 340350. (https://doi.org/10.3892/ijmm.2020.4588)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 92

    Tang X, Li X, Zhang D, Han W. Astragaloside-IV alleviates high glucose-induced ferroptosis in retinal pigment epithelial cells by disrupting the expression of miR-138-5p/Sirt1/Nrf2. Bioengineered 2022 13 82408254. (https://doi.org/10.1080/21655979.2022.2049471)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 93

    Zhang L, Wang Y, Yang D, Zhang C, Zhang N, Li M, Liu Y. Platycodon grandiflorus–An ethnopharmacological, phytochemical and pharmacological review. Journal of Ethnopharmacology 2015 164 147161. (https://doi.org/10.1016/j.jep.2015.01.052)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 94

    Huang J, Chen G, Wang J, Liu S, Su J. Platycodin D regulates high glucose-induced ferroptosis of HK-2 cells through glutathione peroxidase 4 (GPX4). Bioengineered 2022 13 66276637. (https://doi.org/10.1080/21655979.2022.2045834)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 95

    Li C, Li T, Zhu M, Lai J, Wu Z. Pharmacological properties of glabridin (a flavonoid extracted from licorice): A comprehensive review. Journal of Functional Foods 2021 85 104638. (https://doi.org/10.1016/j.jff.2021.104638)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 96

    Hongtao T, Junxian C, Yicong L, Yingshan L, Yunchang Z, Guangzhao L, Lingling L, &Yiqun L. Glabridin, a bioactive component of licorice, ameliorates diabetic nephropathy by regulating ferroptosis and the VEGF/Akt/ERK pathways. Molecular Medicine 2022 28 120. (https://doi.org/10.1186/s10020-022-00481-w)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 97

    Morten Møller P, Jørgensen JOL, Jessen N, Richelsen B, Pedersen SB, Bjørn R, Steen Bønløkke P. Resveratrol in metabolic health: an overview of the current evidence and perspectives. Annals of the New York Academy of Sciences 2013 1290 7482. (https://doi.org/10.1111/nyas.12141)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 98

    Brasnyó P, Molnár GA, Mohás M, Markó L, Laczy B, Cseh J, Mikolás E, Szijártó IA, Mérei A & Halmai R et al.Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. British Journal of Nutrition 2011 106 383389. (https://doi.org/10.1017/S0007114511000316)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 99

    Zhang X, Jiang L, Chen H, Wei S, Yao K, Sun X, Yang G, Jiang L, Zhang C & Wang N et al.Resveratrol protected acrolein-induced ferroptosis and insulin secretion dysfunction via ER-stress-related PERK pathway in min6 cells. Toxicology 2022 465 153048. (https://doi.org/10.1016/j.tox.2021.153048)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 100

    Xin Y, Bai Y, Jiang X, Zhou S, Wang Y, Wintergerst KA, Cui T, Ji H, Tan Y, Cai L. Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 via stimulating the Akt/GSK-3ß/Fyn pathway. Redox Biology 2018 15 405417. (https://doi.org/10.1016/j.redox.2017.12.016)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 101

    Xiang W, Xinxin C, Wenqian Z, Hongbo M, Terigen B, Yike S, Quanwei W, Yi T, Bradley BK, & Qian T. Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways. Acta Pharmaceutica Sinica B 2022 12 708722. (https://doi.org/10.1016/j.apsb.2021.10.005)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 102

    Germoush MO, Othman SI, Al-Qaraawi MA, Al-Harbi HM, Hussein OE, Al-Basher G, Alotaibi MF, Elgebaly HA, Sandhu MA & Allam AA et al.Umbelliferone prevents oxidative stress, inflammation and hematological alterations, and modulates glutamate-nitric oxide-cGMP signaling in hyperammonemic rats. Biomedicine and Pharmacotherapy 2018 102 392402. (https://doi.org/10.1016/j.biopha.2018.03.104)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 103

    Jin T, Cheng C. Umbelliferone delays the progression of diabetic nephropathy by inhibiting ferroptosis through activation of the Nrf-2/HO-1 pathway. Food and Chemical Toxicology 2022 163 112892. (https://doi.org/10.1016/j.fct.2022.112892)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 104

    Fiévet C, Staels B. Combination therapy of statins and fibrates in the management of cardiovascular risk. Current Opinion in Lipidology 2009 20 505–511. (https://doi.org/10.1097/MOL.0b013e328332e9ef)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 105

    Xu N, Wang Q, Jiang S, Wang Q, Hu W, Zhou S, Zhao L, Xie L, Chen J & Wellstein A et al.Fenofibrate improves vascular endothelial function and contractility in diabetic mice. Redox Biology 2019 20 8797. (https://doi.org/10.1016/j.redox.2018.09.024)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 106

    Stephen S, & Noemi L. Fenofibrate for diabetic retinopathy. Asia-Pacific Journal of Ophthalmology 2018 7 422426. (https://doi.org/10.22608/APO.2018288)

  • 107

    Cheng Y, Zhang X, Ma F, Sun W, Wang W, Yu J, Shi Y, Cai L, Xu Z. The role of Akt2 in the protective effect of fenofibrate against diabetic nephropathy. International Journal of Biological Sciences 2020 16 553–567. (https://doi.org/10.7150/ijbs.40643)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 108

    Li S, Zheng L, Zhang J, Liu X, Wu Z. Inhibition of ferroptosis by up-regulating Nrf2 delayed the progression of diabetic nephropathy. Free Radical Biology and Medicine 2021 162 435449. (https://doi.org/10.1016/j.freeradbiomed.2020.10.323)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 109

    Xiaomeng F, Xia G, Shuo W, Mengxiu H, Zhencheng S, Hengbei D, Haitian Y, & Guang W. PPAR-α agonist fenofibrate prevented diabetic nephropathy by inhibiting M1 macrophages via improving endothelial cell function in db/db mice. Frontiers in Medicine 2021 8 652558. (https://doi.org/10.3389/fmed.2021.652558)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 110

    Cheng Y, Zhang J, Guo W, Li F, Sun W, Chen J, Zhang C, Lu X, Tan Y & Feng W et al.Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy. Free Radical Biology and Medicine 2016 93 94109. (https://doi.org/10.1016/j.freeradbiomed.2016.02.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 111

    Danan S, Jin W, Sam T, David M, Ruibing L, Xing C, & Hao Z. Molecular mechanisms of coronary microvascular endothelial dysfunction in diabetes mellitus: focus on mitochondrial quality surveillance. Angiogenesis 2022 25 307329. (https://doi.org/10.1007/s10456-022-09835-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 112

    Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, & Bull S. Inves tigators CT. Canagliflozin and Renal Outcomes in Type 2019 380 22952306. (https://doi.org/10.1056/NEJMoa1811744)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 113

    Shuqin D, Hanqiang S, Lie X, Ping W, &Yanbo S. Canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy. Frontiers in Endocrinology 2022 13 1011669. (https://doi.org/10.3389/fendo.2022.1011669)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 114

    Wenyuan L, Wei L, Yan L, Yonghong X, Rui X, Rong C, & Zhongyuan X. Mechanism of N-acetylcysteine in alleviating diabetic myocardial ischemia reperfusion injury by regulating PTEN/Akt pathway through promoting DJ-1. Bioscience Reports 2020 40 BSR20192118. (https://doi.org/10.1042/bsr20192118)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 115

    Li H, Feng J, Zhang Y, Feng J, Wang Q, Zhao S, Meng P, Li J. Mst1 deletion attenuates renal ischaemia-reperfusion injury: the role of microtubule cytoskeleton dynamics, mitochondrial fission and the GSK3β-p53 signalling pathway. Redox Biology 2019 20 261274. (https://doi.org/10.1016/j.redox.2018.10.012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 116

    Quanwei L, Jianzhao L, Weijin C, Kai Z, Hongji L, Feiyang M, Hui Z, Qingyue H, Jianying G, & Ying L. NAC alleviative ferroptosis in diabetic nephropathy via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2/Gpx4 pathway. Free Radical Biology and Medicine 2022 187 158170. (https://doi.org/10.1016/j.freeradbiomed.2022.05.024)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 117

    Sri Harsha T, &Marc SR. Glucagon-like polypeptide agonists in type 2 diabetes mellitus: efficacy and tolerability, a balance. Therapeutic Advances in Endocrinology and Metabolism 2015 6 109134. (https://doi.org/10.1177/2042018815580257)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 118

    Song JX, An JR, Chen Q, Yang XY, Jia CL, Xu S, Zhao YS, Ji ES. Liraglutide attenuates hepatic iron levels and ferroptosis in db/db mice. Bioengineered 2022 13 83348348. (https://doi.org/10.1080/21655979.2022.2051858)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 119

    An JR, Su JN, Sun GY, Wang QF, Fan YD, Jiang N, Yang YF, Shi Y. Liraglutide alleviates cognitive deficit in db/db mice: involvement in oxidative stress, iron overload, and ferroptosis. Neurochemical Research 2022 47 279294. (https://doi.org/10.1007/s11064-021-03442-7)

    • PubMed
    • Search Google Scholar
    • Export Citation

 

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  • Figure 1

    Three mechanisms of ferroptosis. The regulation mechanism of ferroptosis is mainly related to the regulation of iron metabolism, lipid metabolism, and glutathione metabolism. (ACSL4, acyl-CoA synthetase long-chain family member 4; CP, ceruloplasmin; DMT1, divalent 311 metal transporter 1; FPN, ferroportin; GCL, glutamate cysteine ligase; GPX4, glutathione peroxidase 4; GSH, glutathione; GSS, glutathione synthetase; GSSG, glutathione oxidized; HP, hephaestin; LOX, lipoxygenase; LPCAT3, lysophosphatidylcholine acyltransferase 3; NADPH, nicotinamide adenine dinucleotide phosphate; PL-OOH, phospholipid hydroperoxides; PUFA, polyunsaturated fatty acids; PUFA-CoA, polyunsaturated fatty acyl CoA; PUFA-PL, phospholipid-bound polyunsaturated fatty acids; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; STEAP3, the six-transmembrane epithelial antigen of the prostate 3; TF, transferrin; TFR1, transferrin receptor1).

  • Figure 2

    Ferroptosis plays an important role in heart disease, liver disease, gastrointestinal disease, lung disease, kidney disease, pancreatic disease, retinal disease, brain system disease, and other systemic diseases.

  • Figure 3

    Genes involved in the regulation of ferroptosis in diabetes and diabetic complications.

  • 1

    Jürgen H, & Michael R. Diabetes mellitus–definition, Klassifikation, diagnose, screening und Prävention (update 2019). Wiener Klinische Wochenschrift 2019 131 615. (https://doi.org/10.1007/s00508-019-1450-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, Stein C, Basit A, Chan JCN & Mbanya JC et al.IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Research and Clinical Practice 2022 183 109119. (https://doi.org/10.1016/j.diabres.2021.109119)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Deshpande AD, Harris-Hayes M, Schootman M. Epidemiology of diabetes and diabetes-related complications. Physical Therapy 2008 88 12541264. (https://doi.org/10.2522/ptj.20080020)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM & Yang WS et al.Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012 149 10601072. (https://doi.org/10.1016/j.cell.2012.03.042)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Sonam D, Stephen LL, William CH, & Brent RS. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 2003 3 285296. (https://doi.org/10.1016/s1535-6108(0300050-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Scott JD, Georg EW, Leila SM, Eric DL, Berend S, Manuele R, Giulio S, & Brent RS. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chemical Biology 2015 10 16041609. (https://doi.org/10.1021/acschembio.5b00245)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, Irmler M, Beckers J, Aichler M & Walch A et al.ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nature Chemical Biology 2017 13 9198. (https://doi.org/10.1038/nchembio.2239)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Brent RS, José Pedro Friedmann A, Hülya B, Ashley IB, Marcus C, Scott JD, Simone F, Sergio G, Stavroula KH, & Valerian EK. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017 171 273285. (https://doi.org/10.1016/j.cell.2017.09.021)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Fillebeen C, Lam NH, Chow S, Botta A, Sweeney G, Pantopoulos K. Regulatory connections between iron and glucose metabolism. International Journal of Molecular Sciences 2020 21 7773. (https://doi.org/10.3390/ijms21207773)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Seonghun K, Shin-Wook K, Jeongho J, Seung Hyeok H, Huiyoon S, Bo Young N, Jimin P, Tae-Hyun Y, Gyuri K, & Pureunchowon L. Characterization of ferroptosis in kidney tubular cell death under diabetic conditions. Cell Death and Disease 2021 12 160. (https://doi.org/10.1038/s41419-021-03452-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Hongdong M, Xindong W, Weilin Z, Haitian L, Wei Z, Jun S, &Maowei Y. Melatonin suppresses ferroptosis induced by high glucose via activation of the Nrf2/HO-1 signaling pathway in type 2 diabetic osteoporosis. Oxidative Medicine and Cellular Longevity 2020 2020 1–1 8. (https://doi.org/10.1155/2020/9067610)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Zhou Y The protective effects of cryptochlorogenic acid on β-cells function in diabetes in vivo and vitro via inhibition of ferroptosis. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2020 13 1921–1931. (https://doi.org/10.2147/DMSO.S249382)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Ana S, Tamara S, Milica M, Milica V, Ilijana G, Vesna M, Dragica G, Andjelija I, Ksenija V, & Nevena S. Ferroptosis as a novel determinant of β-cell death in diabetic conditions. Oxidative Medicine and Cellular Longevity 2022 2022 1–19. (https://doi.org/10.1155/2022/3873420)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Antonio B, Andrew RP, Rena LP, Boris G, Anissa FG, Tatsuya K, Karen S, Gregory SK, Stefan RB, &Andreas L. Ferroptosis-inducing agents compromise in vitro human islet viability and function. Cell Death and Disease 2018 9 595. (https://doi.org/10.1038/s41419-018-0506-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Kerins MJ, Ooi A. The roles of NRF2 in modulating cellular iron homeostasis. Antioxidants and Redox Signaling 2018 29 17561773. (https://doi.org/10.1089/ars.2017.7176)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Seibt TM, Proneth B, Conrad M. Role of GPX4 in ferroptosis and its pharmacological implication. Free Radical Biology and Medicine 2019 133 144152. (https://doi.org/10.1016/j.freeradbiomed.2018.09.014)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Bastian K, Thomas P, Anne J, Sigurd L, &Ilir M. The central role of glutathione peroxidase 4 in the regulation of ferroptosis and its implications for pro-inflammatory cytokine-mediated beta-cell death. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 2021 1867 166114. (https://doi.org/10.1016/j.bbadis.2021.166114)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Kenichi S, Rachid S, Anna K, Wan Seok Y, Miki H, Scott JD, Lewis MB, Carlos AV, Adam JW, &Brent RS. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nature Chemical Biology 2016 497503. (https://doi.org/10.1038/nchembio.2079)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Dimitrios G, Alexandra B, &Kostas P. Iron homeostasis and oxidative stress: an intimate relationship. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 2019 1866 118535. (https://doi.org/10.1016/j.bbamcr.2019.118535)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Stockwell BR, Jiang X. The chemistry and biology of ferroptosis. Cell Chemical Biology 2020 27 365375. (https://doi.org/10.1016/j.chembiol.2020.03.013)

  • 21

    Wan Seok Y, Katherine JK, Michael MG, Milesh P, Mikhail SS, &Brent RS. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. PNAS 2016 113 E4966E4975. (https://doi.org/10.1073/pnas.1603244113)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Valerian EK, Gaowei M, Feng Q, Jose Pedro Friedmann A, Sebastian D, Claudette St C, Haider Hussain D, Bing L, Vladimir AT, & Vladimir BR. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nature Chemical Biology 2017 13 8190. (https://doi.org/10.1038/nchembio.2238)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Anthonymuthu TS, Kenny EM, Shrivastava I, Tyurina YY, Hier ZE, Ting HC, Dar HH, Tyurin VA, Nesterova A & Amoscato AA et al.Empowerment of 15-lipoxygenase catalytic competence in selective oxidation of membrane ETE-PE to ferroptotic death signals, HpETE-PE. Journal of the American Chemical Society 2018 140 1783517839. (https://doi.org/10.1021/jacs.8b09913)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Ursini F, Maiorino M, Gregolin C. The selenoenzyme phospholipid hydroperoxide glutathione peroxidase. Biochimica et Biophysica Acta 1985 839 6270. (https://doi.org/10.1016/0304-4165(8590182-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, Roveri A, Peng X, Porto Freitas F & Seibt T et al.Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 2018 172 409422.e21. (https://doi.org/10.1016/j.cell.2017.11.048)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Xinbing S, Ruonan Z, Shuiping L, Ting D, Lijuan Z, Mingming Z, Xuemeng H, Yu X, Xingxing H, &Haoming L. RSL3 drives ferroptosis through GPX4 inactivation and ROS production in colorectal cancer. Frontiers in Pharmacology 2018 9 1371. (https://doi.org/10.3389/fphar.2018.01371)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A & Eggenhofer E et al.Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature Cell Biology 2014 16 11801191. (https://doi.org/10.1038/ncb3064)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z & Shahinfar S et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. New England Journal of Medicine 2001 345 861869. (https://doi.org/10.1056/NEJMoa011161)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Sanchez-Niño MD, Benito-Martin A, Ortiz A. New paradigms in cell death in human diabetic nephropathy. Kidney International 2010 78 737744. (https://doi.org/10.1038/ki.2010.270)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Elmarakby AA, Sullivan JC. Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovascular Therapeutics 2012 30 4959. (https://doi.org/10.1111/j.1755-5922.2010.00218.x)

    • PubMed