Targeting Ferroptosis for Ischemia-Reperfusion Injury

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This entry is adapted from the peer-reviewed paper 10.3390/antiox11112196

Ischemia-reperfusion (I/R) injury is a major challenge in perioperative medicine that contributes to pathological damage in various conditions, including ischemic stroke, myocardial infarction, acute lung injury, liver transplantation, acute kidney injury and hemorrhagic shock. I/R damage is often irreversible, and current treatments for I/R injury are limited. Ferroptosis, a type of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides, has been implicated in multiple diseases, including I/R injury. Emerging evidence suggests that ferroptosis can serve as a therapeutic target to alleviate I/R injury, and pharmacological strategies targeting ferroptosis have been developed in I/R models.

ischemia-reperfusion injury ferroptosis iron antioxidant therapeutic strategies

1. Introduction

Ischemia-reperfusion (I/R) is a pathological condition characterized by the initial restriction of the blood supply to organs or tissues, followed by the restoration of blood flow and reoxygenation. Insufficient blood supply leads to tissue hypoxia and cellular metabolic imbalance, and subsequent reperfusion and reoxygenation cause excessive inflammatory responses and exacerbate ischemic tissue damage, which is known as I/R injury ^[1]. I/R injury is intrinsically associated with oxidative damage, and multiple pathological processes contribute to this damage, including impaired endothelial barrier function, mitochondrial dysfunction, activation of the cell death program, calcium overload, sterile inflammation and autoimmune responses ^[2]. However, the precise molecular mechanism of I/R injury has not been fully elucidated and targeted therapies are still limited. Overall, therapeutic strategies for this condition need to be developed, and examining new therapeutic targets to manage I/R injury is a top priority.

Cell death is a stable pathological indicator of I/R injury. Emerging evidence has revealed a novel therapeutic concept to target regulated cell death (RCD) to counteract I/R injury, although the role of RCD in I/R injury has only recently become apparent ^[3]. Different forms of RCD have been identified in I/R injury, including autophagy, necroptosis, apoptosis, pyroptosis, parthanatos and ferroptosis ^[2]. Recent studies suggest that targeting RCD exerts beneficial effects against I/R injury; in particular, RCD in parenchymal and endothelial cells is recognized as a promising intervention target. I/R injury leads to RCD of parenchymal and endothelial cells, and apoptosis, necroptosis and autophagy are the most common types ^[4]. Generally, regulating I/R-induced RCD has been recognized as a new therapeutic strategy against I/R injury, but effective interventions are rarely summarized.

Recently, ferroptosis, a form of RCD characterized by iron-dependent lipid peroxidation, glutathione (GSH) depletion and glutathione peroxidase 4 (GPX4) inactivation ^[5], has received great attention in I/R events ^[6]. Ferroptosis occurs during the reperfusion but not the ischemic phase, as the levels of two key enzymes in ferroptosis, GPX4 and long-chain-fatty-acid-CoA ligase 4 (ACSL4) in tissues were significantly regulated only during reperfusion, accompanied by elevated iron concentration and malondialdehyde (MDA) levels ^[7]. During the reperfusion phase, mitochondrial respiration is enhanced, which consequently triggers reactive oxygen species (ROS) explosion and ferroptosis ^[8]. Notably, decreased mitochondrial membrane potential (MMP) can be observed, which indicates increased mitochondrial outer membrane permeability, a characteristic of mitochondrial-mediated apoptosis ^[9]. Although caspases are activated during this process, interventions targeting apoptosis do not completely prevent cell death. Thus, although activated in I/R, apoptosis is not essential for subsequent cell death, suggesting the existence of other mechanisms governing cell death ^[10], such as ferroptosis. And indeed, mitochondria play a much more active role in ferroptosis than in apoptosis (17). Moreover, some morphological characteristics of mitochondria during I/R, including reduced mitochondrial volume, reduced or even lost mitochondrial cristae, and condensed mitochondrial membrane densities, are not associated with other forms of cell death, further emphasizing the relevance of ferroptosis ^[8].

2. Therapeutic Strategies Targeting Ferroptosis in I/R Injury

2.1. Ferroptosis in Cerebral I/R Injury

Cerebral infarction, which is also known as ischemic stroke, is an episode of neurological dysfunction induced by the focal cerebral, spinal cord, or retinal infarction ^[11]. Previous studies suggested that ischemic stroke was complicated by iron accumulation in the affected regions, which exacerbated neuronal damage during reperfusion ^[12]. Moreover, iron overload is the major source of oxidative stress in cerebral I/R ^[13], and an adverse prognosis in patients with cerebral ischemia has been associated with elevated brain iron levels ^[14]. Similarly, animals treated with a high-iron diet were more susceptible to middle cerebral artery occlusion (MCAO) ^[15], and iron chelation therapy attenuated I/R injury ^[16].

2.1.1. Therapeutic Targets of Ferroptosis in Cerebral I/R Injury

Iron is an important driver of lipid peroxidation and ferroptosis ^[17]. Tau protein facilitates neuronal iron efflux, the loss of which may result in neurotoxic iron accumulation ^[18]. Tuo et al. ^[19] found that MCAO suppressed tau and increased iron levels in 3-month-old rats and mice, whereas tau knockout did not increase brain iron levels in these mice and protected the hemispheres from I/R injury. However, the protective effect was counteracted and there was accelerated iron accumulation in the brains of aged tau-knockout mice until iron-targeted intervention restored it. Additionally, the ferroptosis inhibitors Fer-1 and Lip-1 attenuated neurological deficits following cerebral I/R. These findings suggest that the tau-iron interaction is a pleiotropic regulator of ferroptosis and cerebral I/R injury. As another key component of iron homeostasis, ferritin has been shown to protect against oxidative injury ^[20], and its degradation has also been demonstrated to trigger ferroptosis ^[21]. A recent study reported that ferritin overexpression exerted a neuroprotective effect against MCAO-induced oxidative hippocampal neuronal death ^[22]. Notably, the increases in p53 and SLC7A11 expression were reversed by ferritin overexpression, suggesting that I/R-induced ferroptosis was suppressed. In addition to cytosolic ferritin, mitochondrial ferritin (FtMt) has also been associated with iron-dependent oxidative damage and ferroptosis ^[23]. In cerebral I/R injury, ferroptosis activation was accompanied by FtMt upregulation ^[24]. FtMt-knockout mice exhibited worsened neurological deficits with typical ferroptosis features after cerebral I/R. Conversely, FtMt overexpression reversed ferroptosis activation and consequently ameliorated cerebral I/R injury. Ferritinophagy is a process in which ferritin is transported to lysosomes for degradation ^[25]. NCOA4 has been demonstrated to promote ferritinophagy ^[26] and further induces ferroptosis ^[27]. Recently, the involvement of NCOA4-mediated ferritinophagy was identified in cerebral I/R, and NCOA4 silencing significantly inhibited ferroptosis and prevented neuronal damage ^[28]. Moreover, NCOA4 was reported to be upregulated by ubiquitin-specific peptidase 14 (USP14) in damaged neurons, and USP14 inhibition effectively decreased NCOA4 levels to suppress ferritinophagy-mediated ferroptosis. These findings provide evidence that targeting ferroptosis by regulating iron metabolism-related proteins/pathways is a potential strategy for ischemic stroke treatment.

2.1.2. Pharmacological Therapies Targeting Ferroptosis in Cerebral I/R Injury

Accumulating evidence suggests that pharmacological interventions inhibiting ferroptosis prevent I/R-induced neuronal damage ^[6]. Since being identified as a master regulator of ferroptosis ^[29], selenium-dependent GPX4 has been associated with brain diseases, including ischemic stroke ^[30]. Alim et al. ^[31] reported that selenium (Se) drove a transcriptional adaptive response to prevent ferroptosis and alleviate hemorrhagic or ischemic stroke. Pharmacological selenium administration augmented GPX4 via coordinated activation of transcription factor AP-2 gamma (TFAP2c) and special protein 1 (Sp1) to inhibit ferroptosis and exert neuroprotective effects, providing a new strategy for stroke management. Recently, the anti-ferroptotic effects of several selenium compounds were characterized in murine models of MCAO ^[32]^[33], further supporting the strategy of using pharmacological selenium to prevent cerebral I/R injury. Some agents with antioxidant or neuroprotective effects have also been reported to inhibit ferroptosis and reduce cerebral I/R injury. Carvacrol (CAR) is a monoterpene phenol with antiproliferative, antiapoptotic, and neuroprotective properties ^[34]. Guan et al. ^[35] demonstrated that CAR protected against I/R-induced hippocampal neuronal impairment by mitigating ferroptosis by increasing the expression of GPX4, providing new insights into the mechanism of CAR-mediated neuroprotective effects on cerebral I/R injury. Rehmannioside A ^[36], bioflavonoids including galangin ^[37], carthamin yellow ^[38] and kaempferol ^[39], have been shown to ameliorate I/R-induced neuronal ferroptosis by upregulating the SLC7A11/GPX4-related axis or inhibiting ACSL4 expression. These findings provide valuable insight into the pathogenesis and available agents for treating ischemic stroke.

2.2. Ferroptosis in Myocardial I/R Injury

Acute myocardial infarction (AMI) accounts for a large proportion of global mortality ^[40]. Although effective myocardial reperfusion strategies are essential for ischemic tissue survival, reperfusion itself may trigger cardiomyocyte dysfunction, which is known as MIRI ^[41]. Emerging evidence suggests that dysregulation of iron homeostasis is involved in the pathogenesis of AMI. Following I/R, excess iron is transported into cells and predisposes cardiomyocytes to undergo ferroptosis via the Fenton reaction and ROS accumulation ^[42]. Precisely targeting ferroptosis has been suggested to be a promising therapeutic option for reversing MIRI, and multiple ferroptosis inhibitors and ferroptosis-regulated genes involved in the MIRI setting have been reported ^[43].

2.2.1. Therapeutic Targets of Ferroptosis in Myocardial I/R Injury

Ferroptosis is closely associated with cellular metabolism and redox machinery. The serum factors transferrin and glutamine have been previously shown to be ferroptosis inducers. Gao et al. ^[44] demonstrated that transferrin and intracellular glutaminolysis are essential for the execution of ferroptosis. The glutaminolysis inhibitor Compound 968 and the iron chelator deferoxamine (DFO) mitigated I/R injury and improved cardiac function in mice, suggesting that targeting glutaminolysis to suppress ferroptosis is a potential therapy for MIRI. As a member of the deubiquitinase family, ubiquitin-specific protease 22 (USP22) has been reported to direct the stabilization of sirtuin-1 (SIRT1) to inhibit p53 transcriptional activity and proapoptotic functions ^[45]. Recently, the USP22/SIRT1 axis was shown to play a pivotal role in ferroptosis-mediated I/R-induced cardiomyocyte damage ^[46]. Increases in USP22, SIRT1, or SLC7A11 attenuated ferroptosis and ameliorated cardiac function, which was accompanied by reduced ROS production, lipid peroxidation and iron accumulation. Intriguingly, in contrast to USP22, ubiquitin-specific protease 7 (USP7) was reported to promote ferroptosis in MIRI by activating the p53/TfR1 pathway ^[47].

As the only known mammalian iron-exporting protein, ferroportin 1 (FPN1) plays a key role in systemic iron homeostasis, and hepcidin-mediated internalization and degradation of FPN1 are critical for maintaining cardiac iron homeostasis ^[48]. As a key regulator of FPN1 transcription ^[49], Nrf2 has been shown to alleviate myocardial injury by inhibiting I/R-induced oxidative damage and cell death ^[50]. Modulation of the Nrf2/FPN1 signaling pathway was shown to be a promising strategy to restrict ferroptosis and alleviate diabetic myocardial reperfusion injury in a recent study ^[51]. Similar to cerebral I/R injury ^[28], ferritinophagy contributes to I/R-induced ferroptosis. DNA (cytosine-5)-methyltransferase 1 (DNMT-1) was shown to affect ferroptosis in diabetic myocardial (DM) I/R by regulating NCOA4-mediated ferritinophagy ^[52]. The increase in ferroptosis was accompanied by elevated DNMT-1 and NCOA4 levels in myocardial tissues in the DM I/R group, while a DNMT-1 inhibitor reversed NCOA4-mediated ferritinophagy and myocardial injury. Moreover, DNMT-1 inhibition enhanced the protective effect of NCOA4-siRNA in a cell H/R model. Therefore, inhibiting DNMT-1 may be a therapeutic strategy for reducing ferroptosis during myocardial I/R by regulating NCOA4-mediated ferritinophagy.

Fragmented oxidized phosphatidylcholines (OxPCs) have been reported to induce cell death in neonatal cardiomyocytes, and several types of OxPCs are increased in models of MIRI ^[53]. Stamenkovic et al. ^[54] recently demonstrated that OxPCs were generated during I/R disrupted mitochondrial bioenergetics and calcium transients and could induce cardiomyocyte death. Notably, GPX4 activity was suppressed in isolated cardiomyocytes treated with OxPCs, which was associated with increased ferroptosis. Furthermore, the neutralization of OxPCs prevented ferroptosis during I/R. Thus, interventions targeting OxPCs may mitigate MIRI. Embryonic lethal-abnormal vision-like protein 1 (ELAVL1) is an RNA-binding protein that regulates gene expression by stabilizing mRNAs ^[55]. Previous studies have suggested its role in pyroptosis in diabetic hearts ^[56] and in ferroptosis during liver fibrosis ^[57]. Chen et al. ^[58] demonstrated that Forkhead Box C1 (FOXC1) transcriptionally activated ELAVL1, increased I/R-induced autophagic ferroptosis, and exacerbated the myocardial injury. ELAVL1 knockdown significantly suppressed ferroptosis and ameliorated pathological damage in mice undergoing myocardial I/R surgery, indicating that ELAVL1 may serve as a target for suppressing I/R-induced ferroptosis.

2.3. Ferroptosis in Lung I/R Injury

Although research remains scarce, recent evidence shows that ferroptosis is involved in lung I/R injury (LIRI) and can be modulated to mitigate lung damage. Xu et al. ^[59] first demonstrated the involvement of ferroptosis in LIRI, and GPX4 and ACSL4 were significantly regulated in lung I/R conditions. Consistent with the findings in other I/R models, increased tissue iron levels, lipid peroxidation and ferroptosis-like mitochondrial morphological changes were observed in the hilar clamp murine model of LIRI. Moreover, the administration of rosiglitazone (ROSI) inhibited ACSL4 expression, decreasing lung I/R-induced ferroptotic damage. Consistent with the findings in intestinal ischemia-reperfusion-induced acute lung injury (IIR-ALI) ^[60], pretreatment with Lip-1 suppressed inflammation and attenuated lung injury following I/R. Irisin is a hormone-like molecule that is mainly secreted by skeletal muscles during exercise, and its anti-inflammatory, antioxidative and antiferroptotic activities have attracted much attention ^[61]. Irisin has been reported to prevent LIRI by restoring mitochondrial function ^[62]. Recently, irisin treatment prevented I/R lung damage by suppressing ferroptosis through the Nrf2/HO-1 axis ^[62], which was similar to the effect of Fer-1. These findings indicate the involvement of ferroptosis in the progression of LIRI. Because of the critical role of oxidative stress in LIRI, inhibiting ferroptosis to attenuate oxidative damage might be a new strategy for preventing I/R lung injury.

2.4. Ferroptosis in Hepatic I/R Injury

2.4.1. Therapeutic Targets of Ferroptosis in Hepatic I/R Injury

Hepatic I/R injury, which commonly occurs during liver surgical procedures, can induce severe liver damage and different forms of cell death, including ferroptosis. A high serum ferritin level in donors is a risk factor for I/R injury in liver transplantation ^[63], and evidence indicates that ferroptosis may be a promising therapeutic target in hepatic I/R injury ^[64]. Not surprisingly, most ferroptosis regulatory targets that have been studied in hepatic I/R are related to iron metabolism. Macrophages play a central role in regulating iron homeostasis and participate in hepatic I/R injury. Macrophage extracellular trap (MET) formation and ferroptosis were more severe both in patients who underwent hepatectomy and mice subjected to hepatic I/R ^[65]. Intriguingly, I/R-induced ferroptosis was reversed by inhibiting MET formation. Additionally, Fer-1 or DFO administration attenuated I/R-induced liver injury, which highlighted the therapeutic potential of inhibiting MET formation and ferroptosis in reversing hepatic I/R injury. The HECT domain-containing ubiquitin E3 ligase (HUWE1) was initially shown to regulate apoptosis ^[66]. However, little is known about the role of HUWE1 in pathological conditions with high levels of cell death, such as hepatic I/R. Wu et al. ^[67] reported an association between high expression of HUWE1 and reduced hepatic injury in liver transplantation patients and further identified HUWE1 as a novel negative ferroptosis modulator that targets TfR1 for ubiquitination and proteasomal degradation to regulate iron metabolism. IREB2 plays a central role in cellular iron homeostasis ^[68] and has been suggested to be a marker gene for ferroptosis ^[5]. Li et al. ^[69] recently reported increased IREB2 expression in a steatotic liver I/R model, and Ireb2 knockdown significantly reduced iron levels and suppressed ferroptosis. Furthermore, miR-29a-3p could downregulate IREB2 expression and inhibit ferroptosis, and the downregulation of miR-29a-3p abolished this protective effect. Fatty livers are extremely sensitive to I/R injury and poorly tolerate this condition, and the authors concluded that targeting Ireb2 via exosomal transfer of miR-29a-3p was a potential preventive strategy.

2.4.2. Pharmacological Therapies Targeting Ferroptosis in Hepatic I/R Injury

To date, few ferroptosis inhibitors have been investigated in hepatic I/R models, and the agents that have been initially validated in other I/R models have not yet been examined in hepatic I/R models. Friedmann Angeli et al. ^[70] discovered that Lip-1 suppressed ferroptosis and reversed liver injury in a preclinical model of hepatic I/R. Similarly, pretreatment with Fer-1 or α-tocopherol (the active form of vitamin E) significantly prevented hepatic I/R-induced ferroptosis-mediated pathological damage ^[63]. Hepatic I/R injury was also attenuated by the iron chelator DFO but was exacerbated in mice that were fed a high-iron diet ^[63]. These results suggest the important role of ferroptosis in the pathogenesis of hepatic I/R injury.

2.5. Ferroptosis in Renal I/R Injury

2.5.1. Therapeutic Targets of Ferroptosis in Renal I/R Injury

Renal I/R injury remains a challenge in perioperative medicine and is closely associated with oxidative cell death. As demonstrated in murine models of I/R-induced AKI, ferroptosis causes synchronized necrosis in renal tubular cells. In addition to the known key enzymes associated with ferroptosis, recent studies have suggested some potential therapeutic targets for I/R-induced ferroptosis, which vary in the mechanisms by which they regulate ferroptosis. Augmenter of liver regeneration (ALR), a widely distributed multifunctional protein, has antioxidant properties ^[71]. Huang et al. ^[72] showed that silencing ALR exacerbated ferroptosis and increased ROS and mitochondrial damage in an in vitro model of I/R-induced AKI. Notably, the researchers demonstrated that ALR mediated ferroptosis in renal I/R injury and was linked to the glutathione-glutathione peroxidase (GSH-GPX) system. Pannexin 1 (Panx1), which is a protein involved in the ATP-release pathway, has a proapoptotic effect on AKI ^[73]. Su et al. reported that Panx1 contributed to ferroptosis-mediated renal I/R injury. Panx1 deletion decreased plasma creatinine and MDA levels and tubular cell death in the kidneys of mice subjected to renal I/R. Moreover, silencing Panx1 expression significantly attenuated iron accumulation and lipid peroxidation induced by the ferroptosis inducer erastin in cultured human kidney 2 (HK2) cells ^[74]. As researchers mentioned previously, ELAVL1 is an important regulator of ferroptosis and has been shown to increase myocardial I/R-induced autophagic ferroptosis ^[58]. Sui et al. ^[75] reported an interaction between ELAVL1 and cold-inducible RNA-binding protein (CIRBP). CIRBP expression was elevated in response to H/R or erastin in HK2 cells, and anti-CIRBP treatment suppressed ferroptosis and improved renal I/R injury. Therefore, CIRBP may promote ferroptosis in renal I/R injury. Legumain, an asparaginyl endopeptidase expressed in proximal tubular cells, is required for the maintenance of kidney homeostasis ^[76]. Legumain deficiency was recently shown to attenuate ferroptosis and tubular injury in renal I/R ^[77]. Mechanistically, legumain participates in the pathogenesis of I/R-induced AKI by regulating the degradation of GPX4, a major ferroptosis-protective factor. Indoleamine 2,3-dioxygenase 1 (IDO) is a rate-limiting enzyme that degrades tryptophan, and inhibiting IDO has been shown to preserve renal function in I/R injury ^[78]. Moreover, IDO expression was upregulated by anoxia and reoxygenation in a H/R model of primary renal proximal tubular epithelial cells (RPTECs) ^[79], which further induced aryl-hydrocarbon receptor (AhR)-mediated ferroptosis and exacerbated H/R damage. Lysine-specific demethylase 1 (LSD1) has been shown to regulate the pathogenesis of kidney disease. In renal I/R injury, LSD1 promotes oxidative stress and ferroptosis ^[80]. However, LSD1 inhibition blocked I/R-induced ferroptosis and oxidative stress by downregulating the TLR4/NOX4 pathway, suggesting that LSD1 is a potential therapeutic target for renal I/R injury.

Several miRNAs have also been identified as important regulators of I/R-induced renal injury. For instance, miR-378a-3p was significantly increased in the urine of rats subjected to renal I/R surgery ^[81]. MiR-182-5p was elevated in posttransplantation AKI patients ^[82], and miR-182-5p inhibition ameliorated I/R-induced renal injury ^[83]. MiRNAs can play functional roles by cooperating with other noncoding RNAs ^[84]. Ding et al. ^[85] found that miR-182-5p and miR-378-3p expression levels were upregulated in H/R-induced injury. Importantly, these two upregulated miRNAs jointly promoted the activation of ferroptosis by downregulating the expression of SLC7A11 and GPX4 ^[85]. Ferroptosis can be regulated by HO-1, which controls the iron level during ferroptotic death ^[86]. Inhibiting miR-3587 (a putative regulator of HO-1) was reported to upregulate HO-1 expression and protect renal cells against I/R-induced ferroptosis ^[87]. These studies provide new insights into targeting I/R-induced ferroptosis to alleviate renal I/R injury.

2.5.2. Pharmacological Therapies Targeting Ferroptosis in Renal I/R Injury

Out of the concern for the potential metabolic and plasma instability of Fer-1, Linkermann et al. ^[88] generated third-generation ferrostatin 16–86 to suppress ferroptosis in renal I/R, which exerted a protective effect even under conditions with severe I/R injury and provided enhanced protection as a combination therapy with mitochondrial permeability transition inhibition. Increasing evidence suggests that pharmacological inhibition of ferroptosis is a promising therapeutic strategy to mitigate renal I/R injury. Inhibitors of ferroptosis, such as XJB-5-131 ^[89], quercetin ^[90], Nec-1f ^[91], Fer-1 and DFO ^[92], have been reported to suppress ferroptosis, thereby attenuating renal injury under I/R conditions. Therefore, postischemic renal necrosis may be targeted by ferrostatin therapy.

Instead of using ferroptosis inhibitors, other pharmacological treatments have been shown to prevent I/R-induced ferroptosis and protect against renal I/R injury. Consistent with the findings in LIRI ^[62], irisin treatment has been proven to alleviate tissue damage in a murine model of renal I/R by upregulating GPX4 expression ^[93]. Pachymic acid (PA), a lanostane-type triterpenoid isolated from Poria cocos, was shown to ameliorate renal damage in a murine model of renal I/R, which may be related to ferroptosis inhibition in the kidney via the upregulation of the Nrf2/HO-1 axis ^[94]. Entacapone, a specific inhibitor of catechol-O-methyltransferase (COMT), has long been used as an adjuvant therapy for Parkinson’s disease. Yang et al. ^[95] recently found that entacapone reversed ferroptosis and alleviated AKI by inhibiting lipid peroxidation and iron accumulation, and the underlying mechanism involves the upregulation SLC7A11 to enhance antioxidant capacity. These findings expand the uses of several existing agents and provide new strategies for the treatment of I/R-AKI.

2.6. Ferroptosis in Intestinal I/R Injury

Some researchers have focused on I/R-induced intestinal injury as well as IIR-induced remote tissue damage. Li et al. ^[96] demonstrated that suppressing ferroptosis with Lip-1 ameliorated I/R-induced intestinal injury. Additionally, inhibiting ACSL4 with ROSI before reperfusion prevented IIR injury, which indicates the role of ferroptosis in IIR. Consistent with findings in cerebral I/R injury ^[97], Sp1 was identified as a critical factor that promoted ACSL4 expression, which could be targeted to alleviate IIR-induced ferroptosis ^[96]. Apigenin-7-O-β-D-(-6″-p-coumaroyl)-glucopyranoside (APG), a flavonoid glycoside extracted from Clematis tangutica, has a strong antioxidant effect on I/R injuries ^[98]. Feng et al. ^[99] demonstrated that APG protected against endothelial ferroptosis and IIR injury by inhibiting MAO-B activation, attenuating ROS generation and decreasing iron accumulation. As important components of the gut, the roles of the gut microbiota and metabolites in I/R-induced ferroptosis and intestinal injury remain unclear. Deng et al. ^[100] reported that the gut microbiota metabolite capsiate (CAT) inhibited ferroptosis during IIR by increasing GPX4 expression through the activation of transient receptor potential cation channel subfamily V member 1 (TRPV1), which provides a potential strategy for the prevention of intestinal I/R damage. Not only in LIRI but the role of ferroptosis has also been studied in the murine model of IIR-ALI. Typical characteristics of ferroptosis, including increased lipid peroxide, decreased reduced GSH and mitochondrial morphological changes were observed in lung tissues of IIR groups. Furthermore, regulation of ferroptosis through the Nrf2-SLC7A11/HO-1 axis ^[101], Nrf2/STAT3/SLC7A11 axis ^[102], Nrf2/TERT/SLC7A11 axis ^[103], as well as an inhibitor of apoptosis-stimulating protein of p53 (iASPP) ^[60], isoliquiritin apioside (IA) ^[104], have been reported to alleviate IIR-induced lung injury.

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