Iron is one of the micronutrients needed by the body for metabolism. Iron’s abnormal content and distribution in the body will affect normal physiological processes ( Figure 1 ). Iron is mostly contained in the body in the forms of Fe²⁺ and Fe³⁺. Ceruloplasmin (CP) oxidizes Fe²⁺ to Fe³⁺ in blood, which combines with transferrin (TF) on the cell membrane and then bounds to transferrin receptor 1 (TFR1) to transport Fe³⁺ intracellularly through endocytosis (12). STEAP3 converts intracellular Fe³⁺ to Fe²⁺ in the endosome. Zinc iron regulatory protein family 8/14 (ZIP8/14) or divalent metal transporter protein 1 (DMT1) mediates Fe²⁺ release into the cytoplasm. In the end, Fe²⁺ is stored in ferritin or iron pools. Ferritin is made up of two chains: a light chain (FTL) and a heavy chain (FTH). FTH contains an oxidase activity that retains iron in the nontoxic Fe³⁺ form (13). Finally, ferroportin 1 (FPN1) transports Fe²⁺ extracellularly to maintain cellular iron homeostasis, which could prevent oxidative damage. The mechanisms of disordered iron metabolism promote ferroptosis that: under weak acid conditions, the presence of free Fe²⁺ can facilitate the formation of lipid peroxides (PLOOH) by transferring electrons to intracellular oxygen and generating alkoxy radicals through the Fenton reaction (14). Additionally, Fe²⁺ can activate certain iron-dependent enzymes involved in lipid metabolism, such as lipoxygenase (LOXs) (15) and cytochrome P450 oxidoreductase (POR) (16), which catalyze the conversion of phosphatidylethanolamine (PUFA-PEs) into PLOOH, thereby inducing ferroptosis.

Research has demonstrated that the dysregulation of iron-related transporters, including DMT1, FPN1, IRP1, and hepcidin, contributes to the accumulation of labile iron within cells and facilitates the occurrence of ferroptosis (17–20) ( Figure 1 ). The phosphorylation of heat shock protein beta-1 (HSPB1) mediated by protein kinase C (PKC) inhibits the iron uptake mediated by transferrin receptor 1 (Tfr1), thereby exerting regulatory control over ferroptosis (21). Furthermore, it suppresses the expression of iron response element binding protein 2 (IREB2), which encodes the important iron metabolism regulators TRFC, FTH1, and FTL, and alleviates ferroptosis sensitivity (5). The intracellular iron content can be modulated by the autophagic breakdown of ferritin, subsequently influencing cellular susceptibility to ferroptosis (22). NCOA4, a nuclear receptor coactivator, facilitates the transportation of ferritin to lysosomes for degradation, resulting in an elevation of cellular Fe²⁺ levels and the induction of ferroptosis. Conversely, the inhibitory effect of ATG5/7 on NCOA4 can impede this process (23). Iron chelation has been demonstrated to inhibit erastin-induced cell death (24). CDGSH iron-sulfur structural domain 1 (CISD1) regulates cellular ferroptosis by mediating mitochondrial lipid peroxidation (25). Moreover, the p62-Keap1-NRF2 pathway can efficiently regulate the generation of intracellular iron ions and ROS, and it also plays a role in ferroptosis regulation (26). These data point to the iron-dependent nature of ferroptosis. The data presented in this study indicate that the regulation of key factors in the intracellular iron metabolism pathway can potentially control the occurrence of ferroptosis.

One of the main causes of cell ferroptosis is the abnormal accumulation of lipid peroxides. Arachidonic acid (AA) and adrenic acid (ADA) are polyunsaturated fatty acids (PUFAs) found in phospholipids (PLs), which readily react with ROS to cause lipid peroxidation (27) ( Figure 1 ). The Acyl-CoA synthetase long-chain family member 4 (ACSL4) preferentially activates PUFAs to form PUFA-CoA derivatives, while LPCAT3 then catalyses the biosynthesis of PUFA-CoA and membrane PEs to phosphatidylethanolamines (PEs), which are finally oxidized to lipid peroxides (PLOOH) by LOXs or PORs (28) ( Figure 1 ). Toxic aldehydes such as 4-hydroxy-2-nonenal (4-HNE) or malondialdehyde (MDA) are produced during lipid peroxide catabolism and combined with continuous oxidation reactions on the cell membrane and plasma membrane. The destruction of lipid membranes, which causes cell death, is known as membrane lipid peroxidation.

Recent research has revealed that ACSL4 is a crucial lipid regulator of ferroptosis in cells (29). Dixon et al. (30). conducted an experiment in which they deactivated ACSL4 and LPCAT3 in the haploid cell line KBM7. They discovered that these cells exhibited resistance to two different GPX4 inhibitors, namely RSL3 and ML162. Sebastian et al. (31). conducted a study in which they established ACSL4 knockout (KO) cells and observed a down-regulation in the sensitivity or resistance of these cells to ferroptosis. However, when these ACSL4 KO cells were supplemented with exogenous AA or AdA (along with other long-chain PUFA), their sensitivity to ferroptosis was restored. Additionally, the researchers successfully constructed ACSL4 and GPX4 double knockout cells, which were able to survive and proliferate for extended periods in cell culture. Notably, it is important to highlight that no other cell type has been able to survive in normal culture without GPX4 thus far. In a separate study, Zhang et al (32). demonstrated that protein kinase CβII (PKCβII) plays a crucial role as a sensor of lipid peroxidation. Upon activation, PKCβII triggers phosphorylation and activation of ACSL4 (pACSL4), leading to the inclusion of PUFA into the PL and subsequent cell death. These findings suggest that the PKCβII-ACSL4 pathway contributes to the process of ferroptosis by amplifying lipid peroxidation. Additionally, the findings demonstrate that the Cadherin-NF2-Hippo-YAP pathway plays a role in determining the sensitivity to ferroptosis by modulating the expression of ACSL4 in response to intercellular contact (33). Consequently, ACSL4 may share more similarities with caspase 3, the executor of apoptosis, rather than a housekeeping protein. This suggests that the activation of fatty acids to COA esters is a crucial regulatory step in the process of ferroptosis. In PE biosynthesis and remodeling, LPCAT3 is crucial. The expression of LPCAT3 was downregulated in the cells, further decreasing the lipid peroxide substrates and eventually preventing cell ferroptosis (30). ACSL4 and LPCAT3, which play a central role in PUFA activation and incorporation into PLs, are thought to be lipid drivers of ferroptosis. P53 is a tumor suppressor gene that controls ferroptosis through the p53-SAT1-ALox15 pathway. SAT1, a transcriptional target of P53, is a crucial speed-limiting enzyme for the breakdown of polyamines. SAT1 activation increases the expression of arachidonic acid lipoxygenase 15 (ALOX-15) while also triggering lipid peroxidation and ferroptosis (34). ACSL4 and LPCAT3, which play a central role in PUFA activation and incorporation into PLs, are thought to be lipid drivers of ferroptosis.

Voltage-dependent anion channel (VDAC) is crucial in controlling ferroptosis because it transfers ions and metabolites ( Figure 1 ). Yagoda et al. (55) found that erastin affects mitochondrial VDACs, altering the membrane permeability and producing a significant release of oxides that ultimately result in cell ferroptosis.

Abnormal adipose tissue differentiation and accumulation often cause central obesity. A High iron environment may cause aberrant differentiation of adipose tissue, which can lead to metabolic dysfunctions (81). Reduction of iron content through knocked down mitoferritin 1 and 2 (Mfrn1/2) in 3T3-L1 preadipocytes (82), knockout of TfR1 and administration of DFO all resulted in abnormal adipocyte differentiation (83), suggesting that iron availability is required for the development and differentiation of adipocytes. Moreover, animal studies have indicated that lowering iron in white adipose tissue can decrease intestinal lipid absorption and protect mice from the metabolic dysfunction caused by a high-fat diet (HFD) (84). Furthermore, there is additional evidence indicating that the inhibition of adipogenic gene expression and reduction of lipogenesis can be achieved by decreasing intracellular iron levels (85, 86). Moreover, high iron levels contributed to the sustained release of adipokines and promoted the formation of an inflammatory environment, recruited macrophages to infiltrate adipose tissue and induced the development of obesity (87). Obesity increased the polarization of M1-type macrophages in mice, and iron accumulation through the production of inflammatory factors (88). In an interesting finding, miR-140-5p which is found in exosomes released by macrophages that invade adipose tissue decreases GSH production by targeting SLC7A11 to cause ferroptosis (89). The chronic inflammatory state associated with obesity, which is characterized by the excessive release of free fatty acids (FFAs) and proinflammatory cytokines from adipocytes, further supports the notion that ferroptosis is intricately linked to obesity (90). Furthermore, iron chelators reduced adipocyte hypertrophy in polygenic obese mice by interfering with the generation of inflammatory agents and ROS and reducing the infiltration of adipose tissue macrophage (ATM) (91). The above findings support the idea that iron homeostasis plays an important role in the development of obesity through its effects on adipocyte differentiation and function. In conclusion, these findings imply that the manipulation of intracellular iron levels could be a viable approach to addressing obesity.

Obesity is the excessive accumulation and storage of fat in the body, which results in various metabolic problems. Adipose tissue dysfunction is closely linked to iron dysfunction ( Figure 2 ). HFD-induced obese mice exhibited higher levels of prostaglandin-endoperoxide synthase 2 (PTGS2) expression and MDA and 4-HNE, as well as lipid ROS and mitochondrial damage (89). ACSL4 and LPCAT3 are lipid drivers that promote the progression of ferroptosis. Elizabeth et al. developed a unique animal model of adipose-specific ACSL4 ablation (Ad-KO), which reduced the levels of PLs, FFAs, and 4-HNE in adipocytes to protect them from increased fat accumulation after feeding HFD (92). It was discovered that in conditionally Lpcat3-deficient mice, there was reduced incorporation of PUFAs (primarily AA) into PLs and redistribution of these FAs to other cellular lipids (e.g., cholesteryl esters) resulted in metabolic disorders and TG accumulation (93). In addition, GPX4 expression was elevated during and necessary for adipocyte differentiation. In several studies, GPX4 overexpression was shown to protect against adipocyte inflammation and hepatopancreatic IR (94). It is noteworthy that Fer-1 treatment mitigated the effects of obesity-induced GPX4 expression (95).Fer-1 reduced iron buildup and lipid peroxidation in HFD-fed mice while increasing SLC7A11 and GPX4 expression (11). These studies suggest that abnormal expression of GPX4, ACSL4 and LPCAT3 in adipose tissue is closely implicated with obesity, and these are also essential regulators of ferroptosis. In conclusion, the preceding results demonstrate that ferroptosis is closely related to obesity, it is suggested that targeting anti-ferroptosis may hold promise as a potential therapeutic strategy for obesity.

The primary pathogenic changes in T2DM are insulin resistance and subsequent progressive secretion defects of pancreatic β-cells, the mechanisms responsible for these are still poorly understood. There is compelling evidence that increases in body iron stores may be associated with T2DM risk (96). This might be linked to impaired insulin secretion, IR, and hepatic gluconeogenesis (97). Insulin resistance (IR) is a complex pathological state characterized by the impaired responsiveness of insulin-dependent cells, such as adipocytes and cardiomyocytes, to normal levels of circulating insulin. This leads to reduced sensitivity of these cells to insulin’s endocrine effects, resulting in diminished uptake and utilization of glucose, the preferred metabolic substrate. The adipocytes secrete various adipocytokines, which regulate whole-body metabolism and homeostasis. Adiponectin and leptin are hormones that are secreted by adipose tissue and regulate insulin sensitivity. Some studies have suggested that under conditions of iron overload, decreased levels of adiponectin (98) and increased secretion of leptin (99) reduce the sensitivity of adipocytes to insulin and lead to insulin resistance (IR). Furthermore, iron-related indicators such as serum ferritin, transferrin, and total iron were evaluated as baseline data in a prospective study, and a positive relationship between IR and baseline serum ferritin levels was discovered after 7 years of follow-up (100). One study demonstrated that DFX selectively stimulated beige fat activation in HFD-induced obese and T2DM mice by upregulating the expression of uncoupling protein 1 (UCP-1), resulting in increased energy expenditure (101). These findings support the notion that elevated iron reserves are linked to adipocyte IR. In addition, there is considerable evidence that iron loading promotes the secretion of inflammatory cytokines by adipocytes (83, 98, 99). TNF-α could prompt IR by increasing the Ser312 phosphorylation of insulin receptor substrate (IRS)-1 (p-Ser312) and decreasing AKT phosphorylation (102). Iron dysfunction leads to mitochondrial dysfunction, which in turn causes IR (103). Moreover, GPX4 knockout animals not only produce adipocyte hypertrophy and macrophage infiltration on their own but also hepatic IR and systemic hypo-inflammation (94). These findings further reveal that iron metabolism problems may disrupt insulin signaling by influencing mitochondrial dysfunction and adipokine production, implying that iron malfunction is implicated in adipocyte IR ( Figure 3 ).

In late diabetes, progressive insulin secretion abnormalities emerge, which may be related to islet cell failure. Existing research indicates that islet iron deposition occurs in T2DM patients, which may be associated with the DMT1 increase in cellular iron intake (104). In a T2DM mouse model, abnormal islet morphology, iron deposition in pancreatic tissue, reduced mitochondrial volume, and cristae loss in pancreatic cells were observed, and quercetin partially reversed these damaging effects, implying a role for ferroptosis in pancreatic β-cell dysfunction (105). In the context of type 2 diabetes mellitus (T2DM), iron deposition in the islet tissue has been observed, leading to increased levels of MDA and 4-HNE. This elevation is attributed to the negative modulation of key regulators of ferroptosis, namely SLC7A11, GSH, and GPX4. However, the administration of liraglutide has shown potential in preventing this iron-induced effect (106). Stimulating human islet β-cells with erastin substantially decreased insulin secretion capability; however, pretreatment with Fer-1 or DFO restored islet cell damage (107). Another study found that the multifunctional iron chelator M30 enhanced islet β-cell function in T2DM mice by elevating cerebral hypoxia-inducible factor (HIF-1α) protein levels, promoting insulin signaling and glucose uptake (108). Curcumin can protect mouse MIN6 pancreatic β-cells against the destructive effects of ferroptosis inducers (109). It is known that Berberine improves T2DM and IR through multiple pathways and inhibits ferroptosis by modulating GPX4 in pancreatic cells (110). Moreover, GPX4 overexpression in mice prevents enhanced FFA-induced ROS and lipid peroxidation (111). Vitamin D (VD) has antidiabetic properties, and 1,25D/VDR has been shown that downregulate the expression of FOXO1 to prevent ferroptosis in pancreatic cells (112). Additionally, FA and FAS exhibited protective effects on MIN6 cells against erastin-induced ferroptosis through the upregulation of the Nrf2 antioxidant pathway (113). Finally, ferroptosis may be related to pancreatic cell secretory failure ( Figure 3 ). There have been fewer investigations on the function of ferroptosis in pancreatic cell destruction, but ferroptosis inhibition may assist in reducing or preventing diabetes and its consequences.

Cardiomyocytes IR and damage result from the endoplasmic reticulum stress (ERS) interacting with ferroptosis. In a diabetic ischemia/reperfusion (I/R) animal model, observing elevated ERS and ferroptosis markers levels, and Fer-1 therapy reduced ERS, on the other hand, ferroptosis was also downregulated after inhibition of ERS, demonstrating the interplay between ferroptosis and the ERS (114). In addition, ERS caused MIN6 cell ferroptosis and malfunction by suppressing the expression of PPAR and enhancing lipid peroxide accumulation (115). Palmitic acid (PA) induces ferroptosis in cardiomyocytes, and overexpression of heat shock factor 1 (HSF1) prevents this damaging effect by reducing PA-induced lipid peroxidation and regulating the expression of iron metabolism-related genes (116). Moreover, ERS can increase the levels of ROS and trigger oxidative stress, promoting IR. Indeed, oxidative stress and ERS indicate that the cellular oxidative system is dominant, which also provides the intrinsic underlying conditions for ferroptosis, implying that may exert synergistic or interactive effects through a common pathway. However, the exact mechanisms of both still require further investigation.

Persistent hyperglycemia results in the formation of advanced glycation end products (AGEs) through non-enzymatic glycosylation. These AGEs bind to their primary cellular receptor, RAGE, and initiate downstream signaling pathways including JNK, MAPK/ERK, TGF-β, and NF-κB (117–119). This activation leads to the induction of oxidative stress and triggers a cascade of inflammatory responses. On the one hand, the activation of the AGEs/RAGE axis initiates intracellular signaling pathways that result in heightened serine phosphorylation and degradation of IRS-1, consequently obstructing the insulin signaling pathway and leading to insulin resistance (120). On the other hand, the signaling mediated by AGEs/RAGE induces escalated oxidative stress and heightened inflammation within pancreatic β-cells. Reactive oxygen species (ROS) can facilitate the generation and accumulation of hazardous IAPP substances, while RAGE interacts with toxic IAPP intermediates and facilitates the formation of amyloid plaques, ultimately causing toxicity in pancreatic β-cells (121). Intriguingly, recent research has indicated that RAGE contributes to the disruption of iron metabolism and is additionally linked to ferroptosis. Through a bioinformatics analysis of periodontitis and type 2 diabetes, two major signaling pathways (immuno-inflammatory pathway and AGE-RAGE signaling pathway) were identified, with ferroptosis being confirmed as a crucial target for the pathogenesis and treatment of T2DM periodontitis (122). A separate study discovered a negative correlation between the expression of RAGE and the accumulation of lipids and inflammation in the liver. The overexpression of RAGE resulted in a significant increase in the upregulation of Tf/TfR, while the expression of FPN1 decreased, indicating an increase in intracellular iron content. RAGE plays a role in regulating the transport and storage capacity of iron. Additionally, RAGE overexpression led to a decrease in GPX4/GSH, the primary antioxidant pathway in cells, and promoted the production of lipid peroxidation products 4-HNE and MDA. This may result in iron overload, heightened lipid peroxidation products, and the exacerbation of ferroptosis in tissue cells (123). The aforementioned studies provide evidence that RAGE plays a pivotal role in the pathophysiology of diabetic complications, potentially establishing a connection between RAGE, iron homeostasis, and ferroptosis ( Figure 3 ). Nevertheless, the existing literature on this subject remains limited, necessitating further investigation into the precise mechanisms involved.

It is widely recognized that atherosclerosis can result in the narrowing or complete blockage of the arterial lumen, leading to inadequate blood supply, tissue hypoxia, and potential cell death in the affected region. Atherosclerosis is characterized by the presence of lipid-rich plaques and necrotic cells, often accompanied by secondary intraplate hemorrhage, plaque rupture, and local blood clot formation. Extensive clinical and foundational evidence has consistently demonstrated that dyslipidemia, hypertension, obesity, and diabetes are primary risk factors for the development of atherosclerosis. The etiology of atherosclerosis remains uncertain; however, the prevailing theory at present is the endothelial damage-response theory. Hypertension has been implicated in the induction of endothelial damage, while low-density lipoprotein cholesterol (LDL-C) can infiltrate the damaged endothelium and undergo oxidation, resulting in ox-LDL-C. Subsequently, monocytes adhere to and penetrate the intima, transforming into macrophages that engulf ox-LDL-C. These macrophages then transition into foam cells, contributing to the formation of lipid streaks, which ultimately evolve into fibrous plaques.

Recent research has also highlighted the association between iron overload and abnormalities in lipid metabolism with these established risk factors. Some investigations discovered abnormal iron status in people with obesity/metabolic syndrome-associated hypertension. For example, hemoglobin and transferrin levels were positively associated with blood pressure and hypertension (124). In vivo, dietary iron limitation was demonstrated to slow the development of hypertension (125). Increased HO-1 expression promotes haem breakdown and ferritin production, changing intracellular iron distribution. The induction of HO-1 lowers blood pressure in hypertension models, due to HO-1 changing the renal tubular and vascular anatomy, altering renal blood flow (126). As previously stated, iron increases the ectopic deposition of fatty lipids. When lipids are deposited in the retroperitoneal, perirenal, and renal sinus adipose tissue, the effect on intrarenal capillary blood flow through the physical compression of the adipose tissue leads to hypertension (127). When lipids are deposited in vascular tissue, they trigger severe vasoconstriction and oxidative damage, leading to increased blood pressure (128). In addition, SNS activation has an important role in hypertension. Sympathetic activation was found to be enhanced in patients with serum iron overload (129). These findings suggested that iron may also significantly influence the development of hypertension via direct or indirect regulation of adipose tissue, iron metabolism, or the SNS system. Furthermore, research has demonstrated a correlation between dyslipidemia and iron overload. Dyslipidaemia is linked to iron overload. Excess iron consumption worsens hyperlipidemia and can lead to dyslipidaemia in hypertriglyceridaemic/hyperlipidaemic rats (130), mice (131), rabbits (132), and zebrafish (133), notably with a considerable increase in triglyceride (TG) levels. Basic research has found that serum lipoprotein lipase (LPL) activity decreases after iron supplementation, and lowering serum iron in Belgrade rats reduces TG levels (134). Moreover, hepcidin is a hormonal regulator of iron homeostasis. Zhang et al (135). found that the serum hepcidin was elevated in a hyperlipidemia model, which suggests the iron burden in hyperlipidemia may be connected to an unbalanced hepcidin-FPN axis. These findings show an essential relationship between iron metabolism problems, particularly iron overload, and dyslipidaemia ( Figure 4 ).

Recently, ferroptosis has been implicated in plaque formation and progression in AS. Studies have found that iron loading can promote AS plaque formation (136). Iron deposition and lipid peroxidation, both of which are hallmarks of ferroptosis, were also identified in advanced atherosclerotic plaques. Inhibition of GPX4 and overexpression of LOXs promote the progression of AS (137, 138). Inhibition of ferroptosis can effectively reduce plaque size and delay the growth of atherosclerotic plaques (139). AS involves complex pathological processes and cell death, including vascular smooth muscle cells, vascular endothelial cells, and macrophages. However, the particular significance of ferroptosis in this setting is uncertain.

The primary cause of AS is endothelial dysfunction. Endothelial cell dysfunction is induced by oxidative damage caused by ROS overproduction. Iron overload was observed to enhance the development of AS in ApoE-/- mice via the ROS pathway (140). Endothelial dysfunction can be caused by oxidized low-density lipoprotein (ox-LDL). In mouse aortic endothelial cells (MAECs), Fer-1 reduced lipid peroxidation and intracellular iron concentrations induced by ox-LDL, whereas SLC7A11 and GPX4 levels increased, suggesting that MAECs can undergo ferroptosis when exposed to ox-LDL (11). The most direct evidence is that erastin can cause vascular endothelial cell (VEC) malfunction to prompt AS via the ROS pathway (141). Additionally, Fer-1 effectively reduced AS in diabetes, which is linked to the haem oxygenase gene (HMOX1) (142). Nrf2 is a key regulator of cellular antioxidant defenses. PDSS2 could drastically reduce ox-LDL-induced ferroptosis in human coronary artery endothelial cells (HCAECs) by increasing Nrf2 expression (143). Taken together, the literature implies that endothelial cell ferroptosis is linked to the pathological process of AS ( Figure 4 ), although further research is needed.

Macrophages are the body’s major immune cells and play an essential role in creating and rupturing AS plaques. Macrophages oxidize and phagocytose low-density lipoprotein and accumulate lipid peroxide (LPO) to form foam cells, which promote plaque formation in early AS (144). Iron accumulation in macrophages can accelerate this process (145). More than half of the mostly dead cells in advanced AS are macrophages, which heighten the inflammatory response and vulnerability of the plaque. In severe AS, foam cells eventually experience nonprogrammed or programmed death, including apoptosis, pyroptosis, necrosis, and ferroptosis, which results in plaque and necrotic core development (146). NCF2, NCF, NCF4, MMP9, and ALOX5 were found to be diagnostic indicators of AS in a recent investigation, and these five markers were mostly related to macrophages. Next, these genes were crossed with ferroptosis, pyroptosis and necroptosis gene sets, and the results revealed that NCF2 and ALOX5 were strongly associated with ferroptosis. This was confirmed by basic experiments, indicating that macrophage ferroptosis plays an important role in atherosclerotic plaque core necrosis (147). Macrophage iron excess can enhance MMP production, resulting in extracellular matrix disintegration and plaque rupture, prompting AS development by boosting the inflammatory response (148). Hepcidin increases intracellular iron levels and decreases serum iron levels. A deficit in hepcidin with low intracellular iron levels in macrophages can slow the course of AS (149). P53 and ATF3 may suppress SLC7A11 expression, reducing GSH production and thereby hastening the course of AS (150). Since HMOX1 is highly expressed in AS and associated with MMP production and macrophage infiltration, it may be a diagnostic biomarker for the disease (151). NOD1 plays an important role in immune defense, and overexpression of NOD1 increases GPX4 levels through CXCR4-dependent signaling (152). Isocitrate dehydrogenase 1 (IDH1) is essential for foam cell production. Ox-LDL substantially elevated IDH1 protein levels and promoted ferroptosis and foam cell formation in macrophages, whereas IDH1 inhibition reversed this result by boosting Nrf2 expression (153). Qingxin Jieyu Granules (QXJYG), a comprehensive herbal formulation for the treatment of AS, inhibited ferroptosis via regulation of the GPX4/xCT signaling pathway, thereby slowing AS development and plaque fragility (139). These results can summarize that macrophage ferroptosis plays an important role in early AS plaque development and in late AS plaque rupture ( Figure 4 ).

Vascular smooth muscle cells (VSMCs) are the main cell type in atherosclerotic plaques at all stages. In the early stages of AS, VSMCs absorb ox-LDL, resulting in foam cell production, and producing chemokines that attract monocytes, which develop into macrophages. VSMCs create an extracellular matrix to form a fibrous cap in advanced AS. Consequently, VSMC mortality may cause fibrous cap thinning and aggravate plaque instability. Cigarette smoke extract (CSE) can induce ferroptosis and upregulate the expression of inflammatory factors in primary rat VSMCs, suggesting that CSE induces VSMC ferroptosis (154). The most direct evidence is the observation of downregulated GPX4 and upregulated PTGS2 and ACSL4 in human coronary AS tissue (155). In contrast, overexpression of GPX4 in ApoE-/- mice delayed the development of AS by lowering lipid peroxidation (156). In addition, VSMCs also participate in vascular calcification to promote atherosclerotic plaque rupture through many mechanisms. Ye et al (157). discovered that high calcium and phosphate concentrations cause iron mortality in rat VSMCs by blocking the SLC7A11/GSH/GPX4 axis and, hence accelerating vascular calcification. In vitro, PA caused VSMC ferroptosis and calcium deposition, while pretreatment with metformin mitigated these effects (158). Additionally, while causing ferroptosis, PA intervention in VSMCs can produce mitochondrial DNA stress, and oleoyl ethanolamide can counteract this harmful impact by activating PPAR, therefore attenuating vascular calcification (159). In conclusion, these findings suggest the active participation of VSMCs in the beginning and progression of AS via ferroptosis caused by several routes ( Figure 4 ).

Numerous studies have indeed highlighted the significant involvement of pyroptosis in AS. Pyroptosis is distinguished by the swift disintegration of the plasma membrane, followed by the liberation of cellular contents and proinflammatory mediators, including IL-1β and IL-18 (160). In cardiovascular disease (CVD), the pyroptosis of vascular endothelial cells disrupts the structural integrity of the vessel wall, consequently facilitating lipid deposition and contributing to the development of AS (161). Additionally, pyroptosis of vascular smooth muscle cells results in plaque instability, rupture, and hemorrhage, thereby elevating the susceptibility to acute coronary syndrome and stroke. Furthermore, monocyte/macrophage pyroptosis exacerbates the inflammatory response and fosters the progression of AS. In contrast to the ferroptosis pathway, pyroptosis is initiated by diverse stimuli, such as high fat and high glucose, which induce mitochondrial dysfunction and subsequent reactive oxygen species (ROS) generation. This ROS production triggers the activation of NF-κB, which subsequently activates the NLRP3 inflammasome. Ultimately, the formation of membrane pores occurs, resulting in cell swelling and rupture, leading to the release of cellular contents and mature inflammatory mediators including IL-18 and IL-1β (162). Consequently, pyroptosis contributes to the promotion of inflammation. The diverse mechanisms of cell death suggest distinct therapeutic targets that hold potential for intervention. The demise of cells may be attributed to the combined impact of various programmed cell death mechanisms, such as necroptosis, pyroptosis, and ferroptosis, thereby influencing diverse pathways and biological functions. Consequently, this observation may offer novel perspectives for the concurrent management of diseases. Subsequently, it becomes evident that this synergy exhibits unforeseen intricacy, thus necessitating a comprehensive exploration of diverse pathways and further investigation into the functional mechanisms and applications thereof.

Recent research has demonstrated that deferoxamine ameliorates obesity in animal models through its ability to diminish iron content in adipocytes, impede the production of inflammatory factors, and mitigate macrophage infiltration, consequently influencing adipocyte differentiation (83, 86). In HFD-fed mice, Fer-1 has been observed to mitigate oxidative stress and lipid peroxidation while augmenting the expression of the SLC7A11/GPX4 pathway (11). Liraglutide is a medication that treats obesity and diabetes by acting on the glucagon-like peptide-1 (GLP-1) receptor. Studies have shown that liraglutide regulates Nrf2/HO-1/GPX4 to prevent hepatic iron mortality in db/db mice (106). In summary, the regulation of iron levels and GPX4 may represent potential therapeutic targets for managing obesity in clinical settings.

Studies have shown that DFO and Fer-1 can restore islet cell damage (107). Quercetin, a flavonoid, has been identified as a natural modulator of iron metabolism. Research has demonstrated that the administration of quercetin can effectively impede iron deposition and significantly restore the content of GDH and the activity of SOD in pancreatic β-cells (105). Similarly, curcumin, berberine, and vitamin D possess antioxidative properties that can ameliorate T2DM and IR, as well as prevent ferroptosis in pancreatic β-cells through various mechanisms (109, 110, 112). These findings suggest that quercetin, curcumin, berberine, and vitamin D hold promise for potential therapeutic benefits in the context of T2DM. Nevertheless, further clinical trials are imperative to ascertain the safety and efficacy profiles of these pharmaceutical agents.

Hypertension, dyslipidemia, diabetes, and obesity have been identified as risk factors for cardiovascular disease. Research has demonstrated that iron overload can contribute to the onset and progression of these risk factors. Consequently, the regulation of iron levels through dietary interventions and pharmacological agents has emerged as a potential therapeutic approach for cardiovascular disease. Three frequently employed iron chelators are commonly utilized in the management of iron overload cardiomyopathy (164). Deferiprone an orally active iron chelator sanctioned by the FDA, specifically acts upon hemorrhagic iron during ischemia/reperfusion events and assumes a cardioprotective function in cases of acute myocardial infarction by eliminating intramyocardial hemorrhage and diminishing myocardial hypertrophy (165). In the context of doxorubicin-induced cardiomyopathy, Fer-1 and dexrazoxane (DXZ) exhibit notable efficacy in mitigating cardiac injury through the preservation of mitochondrial function (166). Furthermore, it was observed that Fer-1 exhibited a reduction in ox-LDL-induced lipid peroxidation in mouse aortic endothelial cells (MAECs) (11). The mTOR pathway, known for its ability to regulate iron metabolism, has been found to safeguard cardiomyocytes against iron overload by targeting various iron transporters (68). Studies have reported that statins can mitigate ferroptosis in animal models of myocardial ischemia-reperfusion and heart failure (167). Additionally, pretreatment with metformin has been shown to attenuate ferroptosis and calcium deposition in vascular smooth muscle cells (158). These findings indicate that ferroptosis assumes a pivotal role in the pathogenesis of cardiovascular disease, and the modulation of iron levels or the utilization of ferroptosis inhibitor-1 represents a promising avenue for the management of CVD.