The peroxidation of PUFAs by lipoxygenases is a key driver of ferroptosis. It has been demonstrated that the mechanism of lipid peroxidation during ferroptosis involves the phosphorylase kinase G2 (PHKG2) regulation of iron availability to LOX enzymes, which in turn drives ferroptosis through the peroxidation of PUFAs at the bis-allylic position. The pretreatment of cells with PUFAs that contain the heavy hydrogen isotope deuterium at the site of peroxidation (D-PUFA) inhibits PUFA oxidation and blocks ferroptosis (38). This indicates that the oxidation of PUFA by LOXs through a PHKG2-dependent iron pool is required for ferroptosis, and that the covalent inhibition of the catalytic selenocysteine in GPX4 prevents the elimination of PUFA hydroperoxides. In a multicenter case-control study on 83 patients newly diagnosed with UC, the authors found that the risk of developing UC was significantly decreased in patients who consumed n-6/n-3 PUFAs, as compared to those who consumed larger amounts of docosahexaenoic, eicosapentaenoic and docosapentaenoic acid (39). However, an earlier study reported that in addition to n-3 PUFAs, both eicosapentaenoic acid and docosahexaenoic acid confer a statistically significant protective effect against the risk of developing UC in a cohort aged >45 years (40). It has also been reported that the PUFA biosynthesis pathway determines ferroptosis sensitivity in gastric cancer, as the expression of elongation of very long-chain fatty acid protein (ELOVL)5 and fatty acid desaturase 1 (FADS1) is upregulated in mesenchymal-type cancer cells, and leads to ferroptosis sensitization (41). These findings implicate PUFAs as key mediators of ferroptosis.

The excessive production and accumulation of ROS induce lipid peroxidation, a key mechanism of ferroptosis. GSH, the reducing substrate of GPX4 activity, is indispensable for preventing ferroptosis (42). The combined effect of GSH/GPX4 protects cells from ferroptotic death, with GPX4 serving as the cornerstone of the antiperoxidative defense. As GSH inhibits the accumulation of ROS, its depletion turns has been shown to be associated with marked lipid peroxidation, dysregulated cellular functions and cell death (43). GSH is synthesized from glycine, L-cysteine and L-glutamate, and the system X_C⁻ cystine/glutamate antiporter, which comprises a light-chain subunit (SLC7A11, xCT) and a heavy-chain subunit (SLC3A2, CD98hc), mainly regulates the exchange of intracellular L-glutamate and extracellular L-cystine. However, certain molecules, such as erastin and sulfasalazine can inhibit system X_C⁻ and cause the depletion of cellular cysteine, leading to the impairment of the intracellular GSH homeostasis and ultimately, intracellular GSH deficiency and ferroptosis (44,45). GPX4 modulates ferroptosis by preventing lipid peroxide-induced toxicity and protecting the membrane lipid bilayers through the conversion of toxic lipid hydroperoxides into non-toxic lipid alcohols (46). On the other hand, RSL3 potently drive ferroptosis by directly targeting and inhibiting GPX4 activity and promoting ROS production (14), as well as through NF-κB pathway activation and GPX4 depletion (47).

Due to the central role played by iron in cell viability and death, cellular iron homeostasis is subjected to exquisite control, mainly through a post-transcriptional network dictated by iron-regulatory protein (IRP)1 and IRP2, which modulate intracellular iron import/export and storage/release (48). Cellular iron is involved in ferroptosis through two major routes. Firstly, the metabolic enzymes implicated in the peroxidation of phospholipids, LOXs and POR, require iron for catalysis; iron is also crucial for a plethora of metabolic enzymes involved in the generation of cellular ROS. LOXs and POR can catalyze enzymatic lipid peroxidation in a Fe²⁺-dependent manner and are implicated in the generation of PLOOH, factors necessary for ferroptosis (49). Secondly, the iron-dependent Fenton chain reaction, a non-enzymatic chemical reaction, is critical for ferroptosis; the inhibition of GPX4 causes PLOOHs to persist longer, triggering the Fenton reaction to rapidly amplify PLOOHs, the hallmark of ferroptosis (25). Moreover, PLOOHs can interact with both ferric and ferrous ions to produce the free radicals, PLOO· and PLO· respectively, which subsequently react with PUFA-PLs to further drive PLOOH production. Therefore, mechanisms that lead to improved ion homeostasis by an enhanced cellular iron export result in a more ferroptosis-resistant cell (50). A previous multicenter, hospital-based case-control study on patients newly diagnosed with UC indicated that the highest intake of iron led to an increased odds ratio for UC in a multivariate analysis, implicating that a high intake of iron has a certain effect on the development of UC (51). It has also been reported that the characteristic iron overload in hereditary hemochromatosis, causes multiple metabolic disturbances, disrupts colonic homeostasis and colon-microbiome interaction, and exacerbates the development and progression of colonic inflammation and colon cancer (52). This may be related to the involvement of excess iron in ROS generation in the intestinal mucosa, enhancing cellular damage and loss of barrier integrity.

Organic peroxides are highly reactive and thermally unstable compounds containing one or more oxygen-oxygen bonds (ROOR) and can undergo self-accelerating decomposition. In this process, the O-O linkage can easily be broken down, releasing free radicals in the form of RO· (alkoxy anions). Organic peroxides are mostly exploited in research models to generate oxidative damage in cells. For instance, tert-butyl hydroperoxide is a typical lipid peroxide analog generally known to stimulate cellular damage due to lipid peroxidation-dependent ferroptosis in human and murine cell lines (53,54). Artemisinin and its derivative compounds, such as artesunate and dihydroartemisinin are 1,2,4-trioxane-based organic peroxides, and effectively sensitize cancer cells to ferroptosis by regulating iron homeostasis (55,56). FINO2, a ferroptosis-inducing organic peroxide containing a 1,2-dioxolane skeleton, indirectly inhibits GPX4 and oxidizes iron. It decreases GPX4 activity and protein levels in vitro, but does not act as an active site, allosteric, or covalent inhibitor of GPX4 or alter GPX homeostasis (57). In other words, FINO2 has a dual induction mechanism for ferroptosis, involving direct iron oxide or indirect inhibition of GPX4 activity. The role of the key mediators of ferroptosis, as described above is illustrated in Fig. 2.

This type of therapeutic agent serves as a scavenger for chain-carrying radicals, thus breaking the self-oxidizing chain reaction. The most common chain-breaking radical-trapping or lipophilic antioxidants are aromatic amines and phenols. For the aromatic amines, ferrostatin-1 and liproxstatin-1 have been demonstrated to function as classical ferroptosis inhibitors in vivo and in vitro (81,82). For example, a previous study demonstrated that the ferroptosis inhibitory activity of ferrostatin-1 and liproxstatin-1 is likely driven by their reactivity as radical-trapping antioxidants rather than their potency as inhibitors of lipoxygenases (81). As previously demonstrated, in a mouse model of DSS-induced IBD, the expression levels of ACSL4 and COX2 were significantly upregulated, while those of GPX4 and FTH1 were downregulated. Treatment with the ferroptosis inhibitors, ferrostatin-1 or liproxstatin-1, mitigated intestinal inflammation by decreasing ACSL4 and COX2, increasing GPX4 and FTH1, and improving mouse body weight and colon length. Moreover, the treatment reduced the expression of Nrf2 and heme oxygenase-1, presenting the suppression of ferroptosis as an effective approach in ameliorating DSS-induced UC in mice (58). Liproxstatin-1 mitigates intestinal barrier injury caused by lipid peroxidation-mediated cell death by inhibiting lipid peroxidation (16).

Ferroptosis has also been demonstrated to participate in the pathophysiology of CD in both human and animal models, indicated by the dysregulation of iron, lipid peroxidation and redox homeostasis. While ACSL4 has been shown to be significantly upregulated and GPX4 to be downregulated in colonic biopsies of patients with CD, other ferroptosis biomarkers, such as MDA, prostaglandin-endoperoxide synthase 2 (PTGS2) and FTH1 are upregulated and GPX4 is downregulated in the colon of the animal model. The administration of ferrostatin-1 in an animal model has been found to alleviate the pathological phenotypes of trinitrobenzene sulfonic acid (TNBS)-induced CD-like colitis (17), providing ferroptosis as a potential therapeutic strategy in treating CD. The role of signal transducer and activator of transcription (STAT)3-mediated ferroptosis, as a ferroptosis-related hub gene, has been reported in in vitro and in vivo models of colitis, where ferroptosis has been found to increase its expression in DSS-induced colitis, Salmonella Typhimurium colitis and in H₂O₂-induced IEC-6 cells. Treatment with ferrostatin-1 reactivates the phosphorylation level of STAT3 (19). The expression of SLC6A14 is significantly elevated and positively correlates with the level of PTGS2 in tissue samples from patients with UC. Moreover, a series of in vivo and in vitro experiments have indicated that the knockdown of SLC6A14 markedly suppresses ferroptosis. Further analysis has revealed that SLC6A14 inhibits the expression of p21 (RAC1)-activated kinase 6 (PAK6) and the knockdown of PAK6 abolishes the effects of SLC6A14 on RSL3-induced ferroptosis in Caco-2 cells. Mechanistically, SLC6A14 promotes ferroptosis in UC by enhancing the expression of CCAAT enhancer binding protein β (C/EBPβ) and its binding activity to inhibit PAK6 (83), providing the SLC6A14-C/EBPβ-PAK6 axis-mediated ferroptosis a potential therapeutic target for colitis.

α-tocopherol, a natural phenolic substance, is the most active form of vitamin E and serves as an effective suppressor of ferroptosis (84). α-tocopherol specifically breaks both peroxidative chain propagation and inhibits lipoxygenases (85). It has been shown that α-tocopherol and GPX4 cooperatively maintain the lipid redox balance and prevent ferroptosis (84). A previous study demonstrated that the deprivation of vitamin E caused the death of GPX4-deficient mice ~4 weeks after the vitamin E-enriched diet was redrawn (86). These findings indicate that the ferroptosis regulator, GPX4, is crucial for cell survival and proper function, and that α-tocopherol can compensate for the loss of GPX4 by protecting cells against deleterious lipid peroxidation. In a preclinical trial, all 14 patients with IBD (with mild and moderately active UC) responded clinically to d-α-tocopherol therapy, with remission induced in nine of them (64%); of note, no adverse events or hospitalization due to worsened disease activity were reported (87). Although several other studies have reported the ability of α-tocopherol to mitigate experimental IBD by protecting intestinal barrier function, modulating the gut microbiota, accelerating intestinal tissue healing and modulating the immune system (88-90), its inhibition of ferroptosis in IBD requires further research. The anti-ferroptotic potential of other synthetic phenolic compounds, such as 1,8-tetrahydronaphthyridinols has been demonstrated, where the inherent radical-trapping antioxidant reactivity of 1,8-tetrahydronaphthyridinols was similarly effective as ferrostatin-1 and liproxstatin-1 at subverting ferroptosis triggered by either genetic or pharmacological inhibition of the hydroperoxide-detoxifying enzyme GPX4 in mouse fibroblasts and hippocampal cells (81). A schematic summary of the various treatments that target ferroptosis in IBD is presented in Fig. 4.

Ion is involved in ferroptosis through either the induction of a non-enzymatic iron-mediated Fenton reaction or the activation of iron-containing lipid oxygenases, such as CYP450/cytochrome P450 oxygenases and arachidonate lipoxygenase (ALOX) (38,91). Thus, potent ion chelators, including deferasirox, ciclopirox, deferoxamine and deferiprone, effectively inhibit ferroptosis-induced cell death. The anti-ferroptotic ability of these ion chelators has been largely explored across many conditions, including intestinal cell injury (37), traumatic spinal cord injury (92), osteoarthritis (93), type 2 diabetic osteoporosis (94), atherosclerosis (95), neuroprotection (96) and acute lung injury (97). In assessing the pathogenic role of ROS in UC, Millar et al (98) examined the influence of exogenous iron (ferric citrate) and iron chelators (desferrioxamine and 1,10-phenanthroline) on the colonic biopsies of patients with UC and normal control subjects. Through luminol-amplified chemiluminescence, they found that desferrioxamine and phenanthroline decreased chemiluminescence by 47 and 26%, respectively in inactive UC, and by 44 and 42% in active UC. Notably, ferric citrate did not affect the chemiluminescence produced by human colonic mucosa, suggesting that there is sufficient free iron in inflamed biopsies already to drive the Fenton reaction maximally (98). Intestinal epithelial cell injury due to ionizing radiation-induced ferroptosis is effectively abrogated by the iron chelator deferoxamine in vitro and in vivo. Moreover, the signs of ferroptosis in intestinal epithelial cells, including the upregulation of intracellular iron levels and lipid peroxidation, the increase in PTGS2 mRNA levels, the downregulation of GPX4 mRNA and GSH levels, and significant mitochondrial damage are significantly relieved by deferoxamine treatment (37).

Deferoxamine and deferiprone significantly alleviate the macroscopic and/or pathological features of inflammation in TNBS-induced colitis by reducing colon weight/length ratio, ulcer index and the total colitis index (99). A recent study reported that ferroptosis was induced in mice with UC, as evidenced by ferrous iron accumulation, elevated ROS production, the depletion of superoxide dismutase (SOD) and GSH, and the reduced expression of GPX-4 and ferritin heavy chain (FTH), accompanied by the increased expression of transferrin (TF). However, deferasirox treatment significantly reversed the changes caused by ferroptotic characteristics in DSS-induced mice and reshaped the composition of intestinal microbiota (100). In another study, the combined administration of deferasirox and vitamin D3 mitigated ion induced-injury by decreasing the levels of pro-inflammatory cytokines (IL-1β/IL-6/TNF-α), oxidative stress (MDA/H₂O₂) and apoptotic markers, but increasing IL-10, GSH, SOD1, catalase and GPX4 levels in rats (101). This indicates that deferasirox enhances cellular anti-inflammatory, anti-oxidative stress and iron regulatory pathways in the inhibition of ferroptosis. However, data on ion chelators in IBD therapy are limited.

ACSL4, an enzyme that converts fatty acid to fatty acyl-CoA esters, is known to dictate ferroptosis sensitivity by shaping cellular lipid composition (27) and contributes to intestinal tissue injury (68). Moreover, the mitochondrial respiratory chain promotes lipid peroxidation by ALOX or POR (cytochrome P450 reductase); thus, ALOX serves as a critical enzyme of lipid peroxidation that leads to ferroptosis (102). Again, the NOXs (nicotinamide adenine dinucleotide phosphate-oxidase) on the cell membranes are a resource of cellular ROS for ferroptosis. Therefore, the inhibition of ACSL4, ALOX and NOXs provides promising therapeutic targets for preventing ferroptosis. Reported enzyme inhibitors include ACSL4 inhibitors, such as thiazolidinediones and triacsin C, ALOX inhibitors such as baicalein, cinnamyl-3,4-dihydroxya-cyanocinnamate, PD146176, zileuton, ML351, AA-861 and NCTT-956, and NOX inhibitors, such as GKT137831, diphenylene iodonium and 2-acetylphenothiazine (38,43). For example, the administration of baicalein ameliorates UC by improving the intestinal epithelial barrier (103) and enhances the normalization of the levels of stress response protein and inflammatory cytokine in the intestine, plasma, and marrow of C57BL/6 mice undergoing mitigation of total-body irradiation (104). Zileuton-fed mice develop fewer intestinal polyps and exhibit a significant reduction in systemic and polyp-associated inflammation (105). Furthermore, the NOX inhibitor, diphenyleneiodonium, and the selective NOX1/4 isoform inhibitor, GKT137831, significantly inhibit erastin-induced ROS production, lipid ROS and cell death (106). Data on the exploration of ferroptosis enzyme inhibition in IBD are limited and provide direction for future studies.

As numerous ferroptosis activators possess the capability of inducing GPX4 degradation, which leads to lipid peroxidation, therapeutic agents that block the degradation of GPX4 enhance antioxidant capacity and inhibit ferroptosis. Typical examples of protein degradation inhibitors are dopamine, 2-amino-5-chloro-N,3-dimethylbenzamide (CDDO) and 5-(tetradecyloxy)-2-furoic acid. These inhibitors block FIN56- or erastin-induced GPX4 degradation to prevent ferroptosis (107,108). For instance, dopamine reduces erastin-induced ferrous iron accumulation, GSH depletion and MDA production through the increase in the protein stability of GPX4, a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation (108). Therefore, a decrease in intestinal dopamine levels is closely related to the development of IBD. Dopamine/dopamine receptor D5 signaling in colonic macrophages controls the development of colitis by modulating M1/M2 macrophage polarization (109) and the activation of the dopamine D2L receptor participates in suppressing colitis-induced weight loss, colon shrinkage, and IL-17 secretion from mesenteric lymph node lymphocytes in response to CD3/CD28 stimulation in mice (110). Therefore, dopamine serves not only as an anti-ferroptotic agent, but also as a potent immune response regulator to ameliorate colitis. In other research, CDDO, a compound known to inhibit heat shock protein 90 (HSP90), was found to potently inhibit both ferroptosis and necroptosis (111). Erastin-activated ferroptosis was found to increase the levels of lysosome-associated membrane protein 2a, also known as CD107b, to promote chaperone-mediated autophagy (CMA), which in turn, promotes the degradation of GPX4. Notably, the inhibition of CMA stabilized GPX4 and reduced ferroptosis (111). These findings suggest that the use of agents that inhibit GPX4 degradation may provide an effective means of mitigating ferroptosis-related lethal effects in IBD.

Stem cells and their derived exosomes have been largely explored as promising therapeutic agents in the treatment of human IBD (112-114) and experimental IBD (115-117). As regards the the targetted treatment of IBD by inhibiting ferroptosis, a recent study confirmed that relative to healthy individuals, patients with UC exhibit higher levels of iron, ACSL4 and MDA, whereas they exhibit decreased levels of GSH and GPX in colon tissues (118). In that study, in the animal model of IBD, exosomes derived from endometrial regenerative cells attenuated the clinical symptoms of colitis and tissue damage by enhancing the expression of GSH and GPX4, but reducing the levels of iron, MDA and ACSL4 in the colons of mice with colitis. Moreover, in vitro analysis revealed that the exosomes rescued erastin-induced cell death and upregulated the levels of GSH and GPX4, while downregulating the levels of iron, MDA and ACSL4 (118). This illustrates the involvement of ferroptosis in the pathogenesis of IBD and the potential of stem cell-derived exosomes to mitigate colitis through the downregulation of intestinal ferroptosis.

In other studies, mesenchymal stem cell-derived exosomes (MSC-Ex) were protected against ferroptosis via the exosomal-mediated stabilization of SLC7A11 in acute liver injury. It was demonstrated that the MSC-Ex triggered the increased expression of SLC7A11 protein, CD44 and OTUB1, and the activation of system X_C⁻ to prevent ferroptosis (119). The stability of SLC7A11 and the consequent activation of system X_C⁻ may partly be attributed to CD44 expression, which suppresses ferroptosis in an OTUB1-dependent manner (120). Moreover, MSC-Ex have been found to inhibit the production of ROS and ferrous iron, upregulate the expression of ferroptosis suppressor FSP1, and enhance the repair of neurological function in mice. Mechanistically, MSC-Ex lncGm36569 prevents ferroptosis-induced neuronal cell dysfunction through the miR-5627-5p/FSP1 axis (121), and MSC-Ex also attenuate renal ischemia/reperfusion injury by interacting with SRSF1 to regulate ASCL4-mediated ferroptosis (122), attenuate myocardial injury by inhibiting ferroptosis in acute myocardial infarction mice (123), and inhibit the ferroptosis of hepatic stellate cells by regulating the xCT/GPX4 axis (124). These observations indicate the promising therapeutic outcomes of the MSC-Ex-induced inhibition of ferroptosis in cell protection. This may provide future direction for research in IBD therapy exploration.

Replenishing cysteine/glutathione deficiency is also an effective method with which to abrogate oxidative stress and its associated lipoperoxidation that characterizes ferroptosis. Thus, the administration of N-acetylcysteine, a cysteine prodrug, replenishes intracellular GSH levels and serves as a safe and well-tolerated antidote for cysteine/GSH deficiency (125). In addition to N-acetylcysteine, oral GSH and sublingual form of GSH also serves as potent GSH supplementation in humans (126). As previously demonstrated, the in vivo administration of N-acetylcysteine attenuates acute TNBS-induced colitis in rats through increased mucosal GSH levels, reducing the extent of intestinal mucosal injury and TNBS-induced ROS overgeneration (127). However, further studies are required to further explore treatments that directly replenish cysteine/glutathione stores as a potential therapy for IBD and other ferroptosis-induced intestinal injuries.

Curculigoside has been shown to alleviate colitis in mice by reversing ferroptosis-related changes, such as iron overload, GSH depletion, excessive ROS and MDA production, and the decreased expression of SOD and GPX4. In IEC-6 cells, curculigoside enhances selenium sensitivity and promotes GPX4 transcription. The selective knockdown of GPX4 significantly inhibits the protective effects of curculigoside on cell death and prevents its downregulation of GSH, MDA, and lactate dehydrogenase activity in ferroptotic IEC-6 (18). The protease furin, a proteolytic enzyme found to exert protective effects in several autoimmune diseases, inhibits DSS-induced ferroptosis-like injury in colon epithelial cells in vivo and in vitro by upregulating GPX4. Mechanistically, furin alleviated the cell injury by activating the Nrf2-GPX4 signaling pathway in mice and NCM460 cells (128). In a recent study, zero-valence selenium-enriched Prussian blue nanozymes (Se-HMPB nanozymes), multifunctional nanozymes capable of scavenging ROS and inhibiting ferroptosis or T-cell differentiation, were explored for IBD therapy (129). The researchers reported that Se-HMPB nanozymes effectively scavenged various ROS in inflammatory tissues and enhanced GPX activity, inhibiting ferroptosis and reversing the lipid peroxidation of intestinal epithelial cells to preserve intestinal barrier integrity in UC. Additionally, the construct inhibited T-cell differentiation in a CD model, regulating the intestinal immune barrier (129), and thus presenting great potential for IBD therapy.

Dipeptidyl peptidase-4 (DPP4) has been implicated in the pathogenesis of IBD and as a potential biomarker (130). It has been shown that TP53 limits erastin-induced ferroptosis by blocking DPP4 activity in a transcription-independent manner. The loss of TP53 prevents the nuclear accumulation of DPP4, and thus facilitates plasma-membrane-associated DPP4-dependent lipid peroxidation, which finally results in ferroptosis (131). In experimental IBD, the DPP4 inhibitor, linagliptin, mitigates colitis by inhibiting colonic DPP4 activity, suppressing colonic IL-6, TNF-α, and myeloperoxidase, and the upregulation of IL-10. Linagliptin also reduces intestinal mucosal oxidative stress by inhibiting lipid peroxides and augmenting GSH, GPX and total antioxidant capacity (132). In similar studies, linagliptin has exhibited promising anti-inflammatory activity against acetic acid-induced colitis through the stimulation of the AMPK/SIRT1/PGC-1α pathway, as well as the inhibition of the JAK2/STAT3 signaling pathway, which may partly be mediated through AMPK activation (133).

Similar to other gastrointestinal diseases, intestinal I/R injury is associated with multiple types of regulated cell death, including autophagy, apoptosis and necroptosis, and the discovery of ferroptosis has triggered the exploration of potential mechanisms of ferroptotic cell death in intestinal I/R injury. ROS generation and lipid peroxidation are associated with intestinal I/R injury and are primary contributors to the initiation and execution of ferroptosis (134). A previous study found that the inhibition of ACSL4, the key enzyme that regulates lipid composition, prior to intestinal reperfusion, protected against ferroptosis and cell death (68). The authors of that study concluded that ferroptosis was closely associated with intestinal I/R injury, and ACSL4 participated in the lethal process, while specificityprotein 1 served as a crucial transcription factor for the increased expression of ACSL4 (68). Depleted GSH levels and a reduced SOD activity, as well as elevated MDA levels, have been observed in animal models of intestinal tissue I/R injury (135,136). These observations implicate the participation of ferroptosis in I/R-induced intestinal injury; however, studies on the underlying mechanisms are largely lacking.

Necrotizing enterocolitis is the most common gastrointestinal disease among newborns and research has established the involvement of several types of regulated cell death in the gut barrier dysfunction that characterizes the disease (137,138). In a previous study, through bioinformatics analyses, ferroptosis was identified to play a role in necrotizing enterocolitis, where ACSL4 gene expression levels were significantly upregulated and positively correlated with ferroptosis, and the influx of multiple immune cells, including macrophages, neutrophils, activated dendritic cells and regulatory T-cells. The inhibition of ferroptosis significantly attenuated necrotizing enterocolitis in newborn mice (69). In other studies, the inhibition of ACSL4 has been proven to be a viable therapeutic approach to preventing ferroptosis-related inflammation, tissue injury, and even tumors (139,140), as ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition (27). Moreover, ROS, a product of ferroptosis, has been found to accumulate in the damaged gut tissues of infants with necrotizing enterocolitis and to serve as a regulatory point (ROS-NF-κB axis) in ameliorating inflammation in necrotizing enterocolitis (141).

The inhibition of ferroptosis as a treatment approach for CAC presents varying outcomes and warrants further investigations. On the one hand, the inhibition of ferroptosis in intestinal tissues by OTSSP167, a MELK inhibitor, alleviates colitis and abrogates the occurrence and progression of CAC by reducing M1 macrophage polarization, macrophage infiltration, downregulating the secretion of pro-inflammatory factors, and significantly repairing intestinal damage. Mechanistically, the treatment inhibits the AKT/IKK/p65 and ERK/IKK/p65 signaling cascades in vivo and in vitro to mitigate colitis and its related colorectal cancer (142). On the other hand, the administration of the ferroptosis inhibitor, ferrostatin-1, results in an increased incidence of CAC. This effect is exacerbated in mice fed a high-fat diet, as they exhibit an increased tumor number and a higher degree of dysplasia following the repression of lipid peroxidation and ferroptosis marker expression in mouse colon tissue (70), providing a new perspective for the prevention of CAC. Additional studies are required in this field to provide clarity and explore the underlying mechanisms. The therapeutic agents, key effects and mechanisms of ferroptosis targets in IBD and other intestinal diseases are summarized in Table I.