The available iron in the body mainly comes from dietary intake and the phagocytosis of senescent red blood cells by macrophages (26). According to the different forms and absorption mechanisms, dietary iron can be divided into heme iron and non-heme iron. Following dietary intake, the duodenum absorbs non-heme iron primarily as Ferric iron (Fe³⁺) at the brush border membrane of epithelial cells. Duodenal cytochrome B (DcytB), potentially in concert with other reductants, ultimately reduces Fe³⁺ to ferrous iron (Fe²⁺). The reduced Fe²⁺ is then transported into the labile iron pool (LIP) within duodenal cells via divalent metal transporter 1 (DMT1) (27). A portion of Fe²⁺ is stored intracellularly in the form of ferritin, which plays a critical role in the strict regulation of iron absorption (28). Simultaneously, the remaining Fe²⁺ is released from the basal membrane of intestinal epithelial cells into the circulatory system via the ferroportin (FPN). The body mainly absorbs heme iron through endocytosis (29). After entering the small intestinal epithelial cells, free Fe²⁺ is released into the cytoplasm by the heme oxygenase-1 (HO-1) and stored in the active iron pool. When the body requires iron, Fe²⁺ is transported to the portal vein by the ferroportin 1 (FPN1) protein. Plasma ceruloplasmin (CP) and other membrane iron transport auxiliary proteins oxidize these iron ions into Fe³⁺. The resulting iron ions then circulate in the plasma as Fe³⁺, binding with transferrin (Tf) to form iron-transferrin complexes (30). The acidic environment of the endosomes promotes the release of Fe³⁺ from Tf, which is then reduced to Fe²⁺ by prostate six transmembrane epithelial antigen 3 (STEAP3) (31). This process maintains iron in a soluble form, enabling its delivery via transferrin receptors to tissues and cells with functional demand.

The gut exhibits precise regulation of iron homeostasis. These regulatory factors maintain iron concentrations within optimal physiological ranges by controlling iron absorption, storage, and utilization. This process directly meets physiological iron demands without inducing the pathological changes associated with iron overload or deficiency. Research on localized intestinal iron metabolism reveals a connection between oxidative stress within the gut and iron-dependent Fenton reactions. During iron overload, excess Fe²⁺ generates substantial reactive oxygen species (ROS) through the Fenton reaction, inducing localized oxidative stress. This heightens susceptibility to the toxic effects of iron overload, disrupting intestinal mucosal homeostasis and triggering local inflammation and cell death, ultimately precipitating the onset of gut-associated diseases (32).

In the intestinal microenvironment of IBD, iron overload or functional iron deficiency not only serves as a source of oxidative stress but also acts as a critical factor triggering ferroptosis in intestinal epithelial cells. When intestinal inflammation disrupts the body’s iron balance, abnormal iron metabolism may lead to the formation of excessive activated iron, causing iron deposition and lipid peroxidation. This heightens susceptibility to the toxic effects of iron overload, disrupting intestinal mucosal homeostasis and triggering local inflammation and cell death, ultimately precipitating the onset of gut-associated diseases (8, 32).

Iron overload-related diseases rank among the most prevalent genetic disorders in humans, characterized pathologically by systemic iron accumulation resulting from excessive dietary iron absorption and iron-induced oxidative stress responses (33). Excess iron catalyzes the production of ROS through the Fenton reaction, disrupting colonic mucosal homeostasis, compromising epithelial integrity, and impairing the gut microbiota interaction. These mechanisms exacerbate colonic inflammation and may even promote colorectal cancer development (34). Conversely, while iron deficiency may partially inhibit pathogen growth by limiting bacterial iron uptake, it simultaneously leads to iron-deficiency anemia and compromises intestinal barrier function (35). As the most common form of anemia globally, iron-deficiency anemia (IDA) develops from chronic iron deficiency, persistent blood loss, or impaired iron absorption (36). Notably, the prevalence of concomitant iron deficiency anemia in IBD patients reaches 6–74% (37). Although iron supplementation is the standard treatment for IDA, its use in IBD patients requires caution. Oral iron supplements may disrupt local iron balance due to intestinal free iron accumulation, which increases oxidative stress and ultimately worsens IBD progression (38).

Ferroptosis is a form of regulated cell death characterized by its high dependence on iron; its core mechanism involves iron ion-catalyzed lipid peroxidation. When excessive iron ions accumulate in cells, the resulting free Fe²⁺triggers Fenton reactions that generate ROS. These ROS then attack phospholipids rich in polyunsaturated fatty acids (PUFAs) on cell membranes, leading to the accumulation of lipid peroxides (LPOs) and compromising membrane integrity (8). Growing evidence suggests that the ferroptosis process is regulated by a complex signaling network involving glutathione (GSH) metabolism, iron metabolism, and the control of oxidative stress (Figure 1).

One of the core characteristics of ferroptosis is the collapse of the antioxidant defense system. Glutathione peroxidase 4 (GPX4), a key enzyme in lipid peroxide repair, reduces lipid peroxides by consuming GSH, thereby converting potentially toxic lipid hydroperoxides into non-toxic lipid alcohols (40). When GPX4 activity is lost, or its substrate GSH becomes increasingly depleted, ferroptosis progresses more rapidly. The Conrad team (41) employed a conditional GPX4 knockout mouse model to investigate the role of GPX4 in ferroptosis, revealing that GSH levels and GPX4 activity are key regulators of this process, whose depletion or inactivation in intestinal tissues leads to unchecked lipid peroxidation and epithelial cell vulnerability, a hallmark observed in IBD patients and experimental colitis models (42). Cystine/glutamate antiporter (System Xc-), acting as a System Xc- on the cell membrane, regulates the upstream pathways of ferroptosis by primarily transporting extracellular cystine into the cell for GSH synthesis. Inhibition of System Xc- using sorafenib reduces cystine uptake and indirectly suppresses GPX4 activity by depleting GSH, thereby inducing ferroptosis (43).

In recent years, understanding of ferroptosis-related mechanisms has progressively deepened. In 2019, Sebastian Doll’s team (44) identified ferroptosis suppressor protein 1(FSP1) as a key molecule mediating ferroptosis resistance via a GPX4-independent pathway. Its expression levels correlate strongly with cellular resistance to ferroptosis. Even in cells lacking GPX4 or GSH, the FSP1/CoQ10 pathway still provides ferroptosis protection, forming a ‘dual safeguard’ for cellular defense. Building upon this, the team further elucidated that FSP1’s inhibitory effect on ferroptosis depends on the mediation of ubiquinone, also known as coenzyme Q10 (CoQ10). FSP1 reduces exogenous CoQ10 to its hydroquinone form (CoQ10H2), which subsequently eliminates lipid peroxides to suppress ferroptosis and ultimately alleviate intestinal ischemia-reperfusion (I/R) injury, establishing the FSP1/CoQ10 axis as a defined molecular mechanism against ferroptosis. Furthermore, the study demonstrates that the anti-ferroptotic effect of CoQ10 in intestinal epithelial cells (IECs) is strictly FSP1-dependent, as FSP1 knockout markedly sensitizes IECs to ferroptosis (45). These findings suggest the potential for the combined use of GPX4 and FSP1 activators or inhibitors to regulate ferroptosis in the treatment of intestinal disorders in a synergistic manner.

The gut exhibits heightened susceptibility to oxidative stress due to its unique physiological structure and function (46). In response to such stress, Nuclear factor erythroid 2-related factor 2 (NRF2) acts as a key transcription factor, coordinating multiple intracellular antioxidant defense systems by directly or indirectly regulating the expression of downstream target genes such as GPX4, thereby safeguarding cells from ferroptosis. Under resting conditions, the KEAP1 protein strictly represses the activity of NRF2. Its protein levels are maintained at low levels through the ubiquitin-proteasome pathway, mediated by Kelch-like ECH-associated protein 1 (Keap1) (47). Meanwhile, the core NF-κB signaling complex (typically composed of RelA, IκBα, and p50 subunits) remains inactive in the cytoplasm. When cells encounter oxidative stress or ferroptosis-inducing stimuli, a series of activation events is triggered (48).

The NRF2 protein initiates multiple activation pathways, including nuclear translocation. On one hand, such stimuli can activate the IKK complex (IKKα/IKKβ/IKKγ) through pathways like TNF-R1–TRAF2 or ROS-RIPK1. Activated IKKβ further phosphorylates Ser32/36 sites on IκBα, leading to its ubiquitin-dependent degradation. This process releases the inhibition on the NF-κB (RelA/p50) dimer, exposing the nuclear localization signal (NLS) of the RelA/p50 dimer and driving its nuclear translocation. On the other hand, the key stress response adapter protein p62 competitively binds to Keap1 through its N-terminal Keap1-interacting region (KIR motif), forming a p62-Keap1 complex. This interaction blocks Keap1’s ubiquitin-dependent degradation of NRF2, stabilizing the protein and promoting its nuclear translocation and transcription of target genes, thereby forming a p62-Keap1-NRF2 positive feedback loop. Nuclear translocation of NRF2 upregulates its own expression and that of the p62 gene (also known as SQSTM1). The newly synthesized p62 protein further binds to and inhibits Keap1, thereby amplifying the NRF2 signaling pathway (49). Following nuclear translocation, NRF2 significantly enhances cellular antioxidant defenses by inducing the expression of downstream antioxidant genes, such as GPX4, GCLC, and GCLM (50).

Activation of the NRF2 pathway effectively suppresses intestinal ferroptosis. In clinical applications, numerous natural compounds, acting as endogenous activators of NRF2, demonstrate significant potential in alleviating intestinal disorders by promoting nuclear translocation and the expression of downstream antioxidant and anti-ferroptotic genes (51). NRF2 activation serves as a fundamental cellular protective response. However, its mechanism of action exhibits considerable complexity. Under conditions such as chronic inflammation or specific tissue microenvironments, NRF2 activation may promote ferroptosis by upregulating genes involved in iron metabolism and lipid peroxidation, particularly when antioxidant defenses are overwhelmed. Research suggests that Astragalus polysaccharides can downregulate overactivated NRF2/HO-1 signaling, restoring redox homeostasis and blocking ferroptosis, thereby alleviating the progression of experimental colitis (52). Thus, whether NRF2 acts as a protector or a promoter of ferroptosis in IBD is influenced by factors such as cellular metabolism, microbial metabolites, and tissue-specific conditions.

Uncontrolled lipid peroxidation is a hallmark of ferroptosis, with Acyl-CoA synthetase long-chain family member 4 (ACSL4) playing a central regulatory role in this process. Through whole-genome CRISPR screening, Dixon’s team (53) identified ACSL4 as a gene essential for GPX4-induced ferroptosis. Emerging evidence suggests that inhibition of ACSL4 alleviates epithelial ferroptosis and subsequent inflammation in IBD models (54). Beyond the ACSL4 pathway, mitochondria also actively participate in the regulation of ferroptosis. Additionally, the regulation of ferroptosis involves other critical systems, such as the tetrahydrobiopterin (BH4)-GCH1 system (55) and the dihydrofolate reductase-reduced coenzyme Q (DHFR-CoQH₂) system (56, 57). FUN14 domain-containing 2 (FUNDC2), a mitochondrial receptor protein, participates in regulating mitochondrial dynamics and metabolic homeostasis.FUNDC2 participates in this regulatory process by interacting with SLC25A11 to modulate mitochondrial GSH levels (58).

The above studies systematically reveal a close connection between ferroptosis and various metabolic pathways, providing a theoretical basis for further understanding its pathological mechanisms in colitis and other related diseases.

Iron overload, as a key inducer of ferroptosis, disrupts cellular iron homeostasis by interfering with critical components of iron metabolism at both transcriptional and post-transcriptional levels, thereby significantly increasing cellular susceptibility to ferroptosis (59). Iron not only constitutes a prerequisite for lipid peroxide accumulation but also directly participates in the execution of ferroptosis (60); in other words, abnormal accumulation of extracellular iron ions under physiological conditions can serve as a natural trigger for ferroptosis.

In IBD, such as UC and CD, accumulation of iron ions has been identified as a key mechanism underlying intestinal epithelial cell damage (61). Inflammatory factors (e.g., TNF-α, IL-6) and ROS associated with IBD impair the capacity of cells to repair lipid peroxidation by inhibiting the activity or expression of GPX4, synergizing with iron overload to significantly lower the threshold for epithelial cells to undergo ferroptosis. Clinical observations suggest that oral iron chelator deferoxamine can promote intestinal epithelial repair and alleviate clinical symptoms in IBD patients (62). Building on these findings, the role of iron ion-mediated ferroptosis in the pathogenesis and treatment of IBD is attracting increasing attention from researchers. The unique regulation of iron homeostasis in the gut serves as a bridge connecting ‘microbial iron regulation’ with ‘local intestinal ferroptosis’.

Acute inflammation constitutes a protective response to infection or tissue injury; yet, excessive or persistent inflammatory reactions may cause tissue damage and even exacerbate disease progression (63). Research by D. J. Cui et al. (64) indicates that the onset of IBD involves the overactivation of ferroptosis. Furthermore, studies have shown that dysregulation of key ferroptosis genes affects disease susceptibility, progression, and severity in the DSS-induced murine colitis model. Clinical trials have demonstrated that ferroptosis inhibitors can significantly alleviate the typical clinical manifestations of IBD, specifically by enhancing intestinal barrier function, promoting weight restoration, optimizing microbial community structure, and reducing the disease activity index (65, 66).

In recent years, research into the regulatory mechanisms of ferroptosis in the progression of intestinal diseases has made significant advancements. Studies have shown that impaired GPX4 function promotes the development of colorectal cancer. Activating GPX4 can significantly reduce ferroptosis in intestinal epithelial cells (IECs) and improve IBD symptoms (66). Relative investigations revealed that the combined use of GPX4 inhibitors and ferroptosis inducers enhances the immunotherapeutic efficacy in colorectal cancer-associated intestinal diseases (67). Additionally, in human and murine IBD models, upregulated ferroptosis-related gene expression and elevated malondialdehyde (MDA) levels confirm the association between ferroptosis and UC (68).

The role of ferroptosis in the pathogenesis of IBD involves multiple pathways, including iron metabolism disorders, intestinal epithelial barrier damage, genetic susceptibility, immune dysregulation, and gut microbiota imbalance. Among upstream regulators of ferroptosis in IBD, hypoxia-inducible factors (HIFs) occupy a unique position by integrating hypoxic stress, iron homeostasis, and inflammatory signaling, thereby setting the threshold at which epithelial ferroptosis is triggered. Intestinal microcirculatory hypoxia is widely recognized as a permissive condition for the onset and progression of UC (69). At the mechanistic level, intracellular iron availability is coordinated by HIF signaling together with iron regulatory proteins (IRPs) (70), linking oxygen sensing to epithelial redox vulnerability.

A central component of this coupling is HIF-2α, an oxygen- and iron-responsive transcription factor that directly regulates key intestinal iron transport genes, including DMT1, Dcytb, and FPN. As a principal transcriptional regulator of intestinal iron transporters, HIF-2α plays a crucial role in maintaining systemic iron balance after birth (71). Importantly, in active intestinal inflammation, HIF-2α may exert context-dependent effects on ferroptosis susceptibility: even under systemic iron deficiency, local inflammatory cues can paradoxically enhance epithelial iron uptake and/or perturb subcellular iron distribution, thereby increasing the labile iron pool and promoting lipid peroxidation. Consistent with isoform specificity, HIF-2α (rather than HIF-1α) enhances iron absorption in mice (72), and human tissue analyses have reported discrete yet overlapping expression patterns of HIF-1α and HIF-2α (73). Although iron-dependent prolyl hydroxylases (PHDs) regulate both isoforms and iron chelation can stabilize HIF-1α and HIF-2α in vitro (74), these observations collectively suggest that the gut may implement additional, tissue-specific mechanisms that bias HIF isoform activity and downstream iron handling.

Beyond iron transport, HIF signaling also shapes IBD through cell-type–specific immune programs, which helps reconcile seemingly conflicting findings across models. HIF-2α has been proposed to alleviate inflammation in certain contexts by reducing intracellular iron overload and limiting ferroptosis. The inflammatory microenvironment in active IBD can markedly upregulate HIF-2α in colonic tissues (75). In parallel, HIF-1α exhibits distinct immune regulatory functions depending on lineage: HIF-1α deficiency in myeloid cells alleviates DSS-induced colitis with increased regulatory T cells (Tregs) (76), whereas HIF-1α deficiency in dendritic cells (DCs) exacerbates colitis with reduced Tregs (77). Conditional knockout studies further indicate opposing roles for myeloid HIF-1α and HIF-2α in DSS colitis, where HIF-1α deficiency ameliorates inflammation but HIF-2α deficiency worsens disease (78). Collectively, these data argue that HIF signaling should not be treated as a single “protective” or “pathogenic” pathway; rather, isoform-, cell type-, and stage-dependent wiring likely determines whether HIF shifts the system toward or away from a ferroptosis-permissive state.

Finally, ferroptosis itself can reinforce HIF activation and disease progression. Ferroptotic injury promotes the release of pro-inflammatory mediators and amplifies oxidative stress (79), which can aggravate microcirculatory dysfunction and hypoxia, thereby reactivating HIF programs and further perturbing iron handling. This establishes a self-reinforcing loop, highlighting why precision strategies targeting iron metabolism and HIF–iron coupling may require careful stratification by tissue niche, inflammatory stage, and cellular compartment in colitis.

Downstream of HIF–iron remodeling, ferroptosis in intestinal epithelial cells (IECs) constitutes a key mechanism that converts upstream threshold shifts into epithelial barrier failure and inflammatory amplification in IBD. At the molecular level, this process is shaped by both genetic programs and disease-associated perturbations in ferroptosis checkpoints. Genetic regulation plays a pivotal role in ferroptosis-mediated IBD pathogenesis. Both clinical IBD patients and the DSS-induced murine colitis model exhibit significant alterations in ferroptosis-associated gene expression profiles (80). Mechanistic studies reveal that inflamed intestinal tissues in IBD patients and corresponding animal models display characteristic ferroptosis features, including GSH depletion, suppression of GPX4 activity, and abnormal iron deposition. Ferroptosis is implicated in IBD, particularly in the death of intestinal epithelial cells (68). Through bioinformatics analysis of UC-related genes, we identified that acyl-CoA synthetase family member 2 (ACSF2) exhibited significantly downregulated expression in DSS-induced colitis models, Salmonella typhi colitis models in mice, and various lipopolysaccharide (LPS)-induced colitis models. Notably, the application of the ferroptosis inhibitor Ferrostatin-1 reversed this phenotype (81). These findings suggest that ACSF2 may alleviate inflammatory responses in IBD and delay the progression of experimental colitis by inhibiting ferroptosis pathways.

Given the critical role of ferroptosis in the pathogenesis of colitis, targeting ferroptosis signaling pathways may become a potential therapeutic strategy for IBD. Currently, certain drugs that alleviate oxidative stress and inflammation by eliminating ROS, such as thioproline and N-acetylcysteine, have been applied in IBD clinical treatments (82), providing valuable references for developing novel ferroptosis inhibitors to improve intestinal diseases.

Immune imbalance is the key amplifier that converts dysbiosis and epithelial stress into sustained inflammatory signaling, which subsequently perturbs iron regulation and favors ferroptosis-prone states. Following the excessive proliferation of pathogenic bacteria, the cytotoxins they secrete can directly damage intestinal epithelial cells (87). Additionally, they may activate pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), thereby promoting the release of pro-inflammatory factors (88). Simultaneously, microbial dysbiosis disrupts intestinal immune tolerance, leading to enhanced Th1/Th17 immune responses while impairing the function of Tregs (89). Research by Read et al. (90) further demonstrates that immune cell dysfunction can lead to intestinal immune regulation disorders. Certain probiotics, however, can restore intestinal immune homeostasis by inducing IgG production and modulating T-cell-mediated immune responses, thereby alleviating colitis (91). For instance, Akkermansia muciniphila in the gut can induce immune homeostasis in mice, promote IgG production, and initiate antigen-specific T-cell responses, thereby improving symptoms of DSS-induced colitis (92).

The impact of genetic polymorphism on IBD is primarily mediated by gut microbiota, highlighting the significance of host genetic variations in disease progression. Genetic factors can modulate the pathogenicity of specific bacteria, with certain pathogens being particularly capable of triggering chronic inflammation under specific genetic conditions (93). Emerging research has also highlighted the critical role of epigenetic and post-transcriptional regulation, particularly through microRNAs (miRNAs), which serve as key modulators of immune responses and microbial interactions in IBD, influencing not only immune modulation but also iron metabolism, oxidative stress, and epithelial integrity, all of which are critical to ferroptosis in IBD (94, 95). To date, genetic research has identified over 100 genetic loci associated with IBD susceptibility, many of which regulate the host’s immune response to bacteria, such as NOD2, TLR5, and IL-10. Taking the NOD2 and CYBB genes as examples, both are susceptibility genes for IBD (96, 97). Mutations in the NOD2 gene are particularly crucial in regulating the pathogenesis of CD’s disease (98). Genetic defects in the innate immune system (such as loss of NOD2 function) lead to dysregulation of the host’s immune response to the gut microbiota, constituting a key driver of chronic inflammation (99).

As a pattern recognition receptor (PRR), NOD2 recognizes bacterial peptidoglycan and regulates the expression of antimicrobial peptides by activating the NF-κB signaling pathway, thereby promoting their production. Notably, NOD2 gene mutations are closely associated with structural alterations in the gut microbiota, further demonstrating that IBD development depends on the interaction between the genetic background and microbial communities (100). In individuals with NOD2 mutations, the gut microbiota exhibits compositional and diversity dysregulation, characterized by a decreased abundance of certain beneficial bacteria and an excessive proliferation of harmful bacteria, which may exacerbate intestinal inflammatory responses. Additionally, under specific pathogen-free (SPF) conditions, H. hepaticus can induce chronic colitis in IL-10−/− mice, whereas no corresponding pathological changes were observed in wild-type mice (101).

In the process by which pathogenic symbionts (pathobionts) induce IBD, the stability of the gut microbiota is crucial. Under healthy conditions, commensal bacteria and pathogens within the gut maintain an appropriate dynamic equilibrium. The microbiota regulates the expression of tight junction proteins (such as ZO-1 and occludin) in intestinal epithelial cells by releasing specific metabolites and signaling molecules, thereby safeguarding the structural and functional integrity of the intestinal barrier (86). In IBD patients, significant dysbiosis frequently occurs. This imbalance leads to downregulation of tight junction protein expression, increased intestinal mucosal permeability, and the initiation and exacerbation of inflammatory cascades. For instance, studies reveal an expansion of mucus-degrading bacteria (such as Akkermansia) in the gut of IBD patients. The mucin-degrading enzymes secreted by these bacteria disrupt the mucus layer’s structure, leading to heightened intestinal mucosal permeability (102). Concurrently, the compromised intestinal barrier facilitates the translocation of microbial components, including LPS and flagellar proteins, along with secondary bile acids, into the systemic circulation, thereby triggering systemic inflammatory responses (103). Studies have also revealed that astragaloside IV, derived from traditional Chinese medicine, can enhance the abundance of Akkermansia muciniphila, repair intestinal mucosal barriers, improve the gut immune environment, and reduce LPS blood entry, thereby suppressing systemic inflammatory responses (104).

Studies demonstrate that when TLR5^–/– germ-free mice are infected with adherent-invasive Escherichia coli (AIEC) and subsequently exposed to a specific SPF microbial environment, they develop colitis symptoms (105). In contrast, mice inoculated with the altered Schaedler flora (ASF), a pathogen-free microbial community, exhibit no significant intestinal inflammation after AIEC infection (106). This suggests that AIEC induces chronic intestinal inflammation in susceptible hosts by promoting microbial dysbiosis. Specifically, this pathogenic process depends on a complex microbiota defined by specific species, functions, and interactions. Clinical studies indicate that AIEC exhibits synergistic effects during pathogen infection; its colonization exacerbates clinical outcomes in Salmonella typhimurium-induced infectious gastroenteritis, suggesting pathogenic bacteria may modulate acute infection progression (107).

The gut microbiota of IBD patients exhibits a trend towards reduced diversity, manifested explicitly by a decrease in the abundance of commensal Clostridia and a significant enrichment of pathogenic bacteria. These pathogenic bacteria can colonize the gut by exploiting epithelial damage and activate TH1/TH17 immune responses through virulence factors, such as the type III secretion system (108). Meanwhile, fungal species such as Candida and Malassezia secrete candidalysin, which activates IL-1β, thereby exacerbating inflammatory responses (109). Research by G. Pontarollo’s team (102) has revealed a novel mechanism by which gut microbiota modulate intestinal barrier function: symbiotic bacteria activate TLR-2 signaling in the innate immune receptors of intestinal epithelium, thereby downregulating neuropilin-1 (NRP1) and the Hedgehog signaling pathway it regulates, thus impairing intestinal barrier function.

The data mentioned above indicate that the pathogenic potential of specific microorganisms in IBD is subject to multifactorial regulation, encompassing genetic background, environmental factors, and the composition of the gut microbiota. Diet, as another critical determinant, can rapidly modulate the structure and function of the microbiota, thereby exerting specific effects on the pathogenesis of IBD. Research indicates that a high-fat diet can promote the proliferation of pro-inflammatory Enterobacteriaceae by altering bile acid metabolism, thereby inducing pathogenic translocation (110). In IBD mouse models, high-fat and high-sugar feeding lead to dysbiosis, manifested as excessive proliferation of Escherichia coli, accompanied by destruction of the mucosal layer structure and increased intestinal permeability (111).

Interestingly, the gut virome, consisting of a variety of viruses, also contributes to microbial dysbiosis and immune modulation in IBD. Studies suggest that viral communities can interact with gut bacteria, potentially exacerbating inflammation or influencing immune cell behavior (112). Although most studies have concentrated on bacterial dysbiosis, the virome is emerging as an essential player in the pathogenesis of IBD. Exploring the interactions between bacterial and viral communities in the gut may uncover novel therapeutic targets for modulating the immune system and restoring intestinal homeostasis (113).

Iron competition in the gut is a core ecological force that links microbial fitness to host ferroptosis susceptibility. Using high-throughput screening of microbial metabolites, Das et al. (115) reported that microbiota-derived metabolites suppress HIF-2α, a master regulator of intestinal iron absorption, and increase ferritin levels, thereby limiting host iron uptake and potentially reducing the labile iron pool that fuels lipid peroxidation. Related research has demonstrated that Candida albicans accelerates atherosclerosis by activating intestinal HIF-2α signaling (116). Another piece of evidence that intestinal oxygen dynamics plays a key role in ferroptosis-mediated microbe-host interactions is that the oxygen gradient established in the gut under physiological conditions is crucial for maintaining microbial ecological balance. When elevated host oxygenation disrupts the intestinal radial oxygen gradient, it alters the microbial composition, promoting the enrichment of oxygen-tolerant bacteria while significantly suppressing strict anaerobes, such as Anaerostipes, which produce SCFAs (117). Because SCFAs and other anaerobe-associated metabolites contribute to epithelial redox homeostasis, oxygen-driven community shifts may lower antioxidant buffering and thereby increase ferroptotic vulnerability during inflammation (118).

Ferroptosis is driven by an iron metabolism imbalance and antioxidant system collapse, with immune cells exhibiting high heterogeneity in the response process. The gut microbiota influences ferroptosis by modulating the intestinal antioxidant system, serving as a key factor in the pathogenesis and progression of ferroptosis in IBD. The differential susceptibility of various immune cells to ferroptosis determines their roles in iron homeostasis and antioxidant defense. For instance, Dendritic cells (DCs) play a critical role in antitumor immunity by activating T cells, yet ferroptosis inhibits DC maturation and impairs their antitumor function (119). RSL3-induced ferroptosis leads to the loss of DCs’ ability to secrete pro-inflammatory cytokines and further suppresses T cell activation. Proliferator-Activated Receptor Gamma, PPARγ (PPARG/PPARγ) plays a central role in this process, and knockout of PPARG restores DC function (120). Macrophages and intestinal epithelial cells play critical roles in iron metabolism, which can mediate ROS generation (121). While the function of T cells depends on the iron environment. Compared to effector T cells, regulatory T cells (Tregs) exhibit a greater preference for lipid metabolism and demonstrate resistance to ferroptosis, whereas effector T cells rely on glutamine metabolism, rendering them more susceptible to ferroptosis (122). By knocking out ACSL4 in T cells, D. J. Collins et al. found that reduced levels of PUFA-PLs could promote resistance to ferroptosis, while decreased PUFA-PLs in neutrophils could enhance ferroptosis susceptibility, indicating that PUFA-PLs are the primary factors determining ferroptosis sensitivity in lymphocytes and myeloid cells (123).

At the antioxidant level, commensals can reinforce host redox buffering. For example, Bifidobacteria metabolize and produce antioxidant substances such as vitamin K and GSH precursors, which can reduce cellular sensitivity to ferroptosis by regulating lipid metabolism (124). When pathogenic bacteria invade, they effectively mitigate lipid peroxidation-induced PUFA oxidative damage caused by LPS (125). Another metabolic product of intestinal bacteria, urolithins (UA), is produced through the conversion of dietary ellagitannins and ellagic acid by specific gut microbiota. It can activate the Keap1–NRF2/HO-1 axis to suppress lipid peroxidation and ferroptosis (126), and can also enhance mitophagy and dampen excessive inflammation (127), processes that may converge on ferroptosis control. Microbial signals can also affect epithelial stress-response pathways. Intestinal-origin Lactobacillus rhamnosus GG (LGG) activates the intestinal epithelial AKT-STAT signaling pathway, helping to restore a balanced gut microbiota, promote intestinal epithelial cell proliferation, and repair damage (128). In addition, capsaicin (CAP), another gut microbiota metabolite, alleviates ventilator-induced lung injury by activating Sirtuin 3 (SIRT3) to inhibit ferroptosis and maintain mitochondrial redox homeostasis (129).

In summary, Current studies suggest that certain monomeric components derived from traditional Chinese herbal medicines may exert protective effects through mechanisms such as modulating gut microbiota, improving the microenvironment, alleviating oxidative stress, and inhibiting ferroptosis. Paeoniflorin (PA), a monomeric component of traditional Chinese medicine, improves impaired glucose tolerance and myocardial injury symptoms. It exhibits potent effects against ferroptosis and modifies the composition and structure of the gut microbiota, offering protective benefits in diabetic cardiomyopathy mice (130). Zhang et al. (131) demonstrated that supplementing with Lachnospiraceae bacterium strains significantly alleviated neutrophil infiltration and oxidative stress in ethanol-exposed mouse livers, exhibiting remarkable hepatoprotective effects. The differential metabolite N-acetylglutamate (NAG) activates the KEAP1-NRF2 pathway and concurrently inhibits ferroptosis, thereby mediating a protective effect. However, these findings are primarily based on models such as diabetic cardiomyopathy or liver injury. Translating them into effective strategies for the prevention or treatment of IBD remains a promising scientific hypothesis that urgently requires direct validation of efficacy and specific mechanisms in IBD animal models and clinical studies.

Collectively, accumulating studies suggest that the “microbiota–metabolite–ferroptosis axis” contributes to IBD pathogenesis (Table 1) (132). Below, we highlight representative microbiota-dependent metabolites that modulate ferroptosis-relevant nodes (iron handling, lipid peroxidation, antioxidant systems) and discuss their translational potential.

Ferroptosis reshapes the gut microbiota composition by altering the intestinal microenvironment. This may subsequently induce alterations in local gut microbial structure and metabolic products, thereby establishing and exacerbating a vicious cycle of ferroptosis. Relevant mechanisms involve iron metabolism disruption, oxidative stress, intestinal barrier damage, and immune microenvironment imbalance. Under pathological conditions, ferroptosis causes intestinal epithelial damage, characterized by crypt disruption, a reduction in goblet cells, and degradation of tight junction proteins. This compromised barrier function facilitates bacterial translocation while recruiting and activating pro-inflammatory immune cells, such as neutrophils and Th17 cells, thereby intensifying the inflammatory process (180).

Cells undergoing ferroptosis release substantial amounts of labile iron. A high-iron environment promotes the growth of certain pathogenic bacteria while suppressing the growth of beneficial ones. Gu et al. (181) established a high-iron diet mouse model, demonstrating that iron overload significantly increases iron levels in serum, colonic tissue, and feces, and successfully induces colitis phenotypes and ferroptosis. Non-targeted fecal metabolomics analysis revealed significant metabolic differences between iron-deficient, normal, and iron-overloaded groups. Both iron deficiency and iron overload-induced metabolic disorders are closely associated with the genus Dubosiella, with specific genera, such as Akkermansia and Alistipes, showing significant correlations with colitis severity. Iron overload mediates colitis development in mice by simultaneously activating intestinal epithelial cell ferroptosis and disrupting gut microbiota homeostasis. Concurrently, microbial dysbiosis reduces the production of beneficial metabolites such as SCFAs, further compromising intestinal epithelial energy supply and anti-inflammatory defenses.