Ferroptosis: A therapeutic opportunity of inflammatory bowel disease

To the Editor: Even to this day, the etiology and pathogenesis of inflammatory bowel disease (IBD) are still unelucidated. Despite significant progress in IBD treatment in recent years, some patients remain insensitive or non-responsive towards existing treatments. Therefore, further exploring IBD pathogenesis to develop novel therapeutic drugs or drug combinations is quite necessary. Recent studies have demonstrated the therapeutic potential of regulating cell death in IBD. The ferroptosis, a novel form of cell death, is also involved in the pathological process of IBD.1 Term of ferroptosis was coined in 2012, and it is characterized by morphological, biochemical, and genetic features that distinguish it from other forms of cell death. The overview of ferroptosis is provided in Supplementary Figure 1, https://links.lww.com/CM9/B954. In addition, ferroptosis is closely associated with the occurrence and development of many diseases, such as immune disorders. Some studies have depicted that inducing ferroptosis could benefit rheumatoid arthritis patients. However, inhibiting ferroptosis may benefit patients with certain disorders, such as systemic lupus erythematosus and autoimmune hepatitis.2 Besides, ferroptosis exerts an impact on immune cells. On one hand, ferroptosis directly influences the quantity and functionality of immune cells. On the other hand, immune cells identify ferroptotic cells, thereby triggering inflammatory responses.3 The pathogenesis of IBD is closely linked to disturbances in glutathione (GSH) homeostasis, excessive iron accumulation, lipid peroxidation (LPO), and other hallmarks associated with ferroptosis. Supplementary Table 1, https://links.lww.com/CM9/B954 presents the available ferroptosis reagents that can be used to induce the IBD models. Moreover, accumulating evidence indicates that controlling the pathways associated with ferroptosis could offer promising therapeutic potentials for patients with IBD. Potential association of ferroptosis with IBD: GSH inhibits ferroptosis at optimal intracellular concentrations, and glutathione peroxidase 4 (GPX4) prevents ferroptosis by inhibiting intracellular peroxidation lipids. The IBD patients and experimental colitis models exhibit depletion of GSH and inactivation of GPX4 in colon tissues, while supplementation with GSH and enhancement of GPX4 activity may alleviate colitis. The curculigoside was reported to relieve the experimental colitis by inducing GPX4 to inhibit ferroptosis.4 With the advancement of research, several nanomaterials have been synthesized for the regulation of ferroptosis. For instance, considering the association between GPX4 activity and selenium status, zero-valence selenium-enriched Prussian blue nanozymes was developed, which can alleviate colitis by enhancing GPX4 and suppressing ferroptosis in ulcerative colitis (UC).5 Iron is crucial for maintaining normal cellular function as an indispensable micronutrient in the body. However, excess levels of iron can exacerbate chronic inflammation, including IBD. The accumulation of iron can disrupt homeostasis and give rise to cellular damage. Specifically, excess iron produces poisonous hydroxyl radicals with higher activity through the Fenton reaction. Excess free ferrous iron can be stored in ferritin, a protein composed of two chains: ferritin light chain (FTL) and ferritin heavy chain (FTH). The regulation of intracellular iron content by ferritin maintains an indicative role in ferroptosis. A recent study demonstrated that deferasirox, an iron chelating agent, can increase the expression of FTH and ameliorate experimental colitis.6 In studies related to IBD, supplementation of polyunsaturated fatty acid (PUFA) can disrupt balance of intestinal environmental and lead to intestinal side effects. In contrast, controlling PUFA intake delay IBD progression. The oxidation of PUFAs in biofilms is called LPO, of which acyl-CoA synthase long-chain family member 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and arachidonic lipoxygenase (ALOXs, particularly ALOX15) mediate lipid toxicity in ferroptosis. A recent study conducted on a model resembling Crohn's disease (CD) illustrates the impact of PUFAs and ACSL4 on CD development. Specifically, a Western diet rich in PUFAs results in focal granulomatous alterations in the colon tissue of mice lacking one GPX4 allele within the intestinal epithelial cells (IEC) (GPX4+/–IEC).7 Transcription factors and ferroptosis in IBD: Targeting crucial mediators of ferroptosis is imperative for regulating the intricate process in IBD. Moreover, several transcription factors, such as nuclear factor erythrocyte 2-related factor 2 (Nrf2), nuclear factor κB (NF-κB), and signal transducer and activator of transcription 3 (STAT3), coordinate susceptibility to ferroptosis through transcription-dependent or non-transcriptional mechanisms Supplementary Figure 2, https://links.lww.com/CM9/B954. Nrf2, encoded by the NFE2L2 gene, exhibits ubiquitous expression in a wide range of eukaryotic cells, and plays a crucial role in regulating redox dynamic balance through its binding affinity to antioxidant reaction elements (ARE). In unperturbed circumstances, Nrf2 maintains low cytoplasmic level through its interaction with Kelch-like ECH-associated protein 1 (Keap1). Nrf2 dissociates from Keap1 and translocates to the nucleus during oxidative stress in vivo, binding to ARE and activating downstream target gene expression. It is believed that Nrf2 plays a bidirectional regulatory role in ferroptosis. Specifically, Nrf2 regulates the expression of FTH, FTL, heme oxygenase 1 (Hmox1, HO-1), glutamate-cysteine ligase (GCLC), solute carrier family 7a member 11 (SLC7A11), and GPX4. Increasing evidence showed the remarkable potential of targeting the Nrf2 pathway in IBD. Ferroptosis has been observed in a colitis model induced by dextran sulfate sodium salt (DSS). The expression levels of Nrf2 and HO-1 are increased in DSS mice, which can be reversed by Fer-1, a ferroptosis inhibitor, as well as Astragalus polysaccharide.8 In addition to the Nrf2/HO-1 pathway, the Nrf2/GPX4 pathway is also restrained in UC. Furin can enhance GPX4 expression by activating Nrf2, thereby ameliorating experimental colitis.9 Transcription factor NF-κB, a pivotal class of transcription factors, comprises five subunits. The phosphorylation of the p65 subunit serves as an indicator for the transcriptional activity of NF-κB. Recent research has also indicated that NF-κB plays a significant role in modulating ferroptosis. Phosphorylated NF-κBp65 inhibits endoplasmic reticulum (ER) stress by interacting with eukaryotic translation initiation factor 2α (eIF2α) and alleviates ferroptosis in IEC. This is characterized by the higher level of IEC necrotic cells, ferrous iron amounts, and reactive oxygen species (ROS) in IEC-specific NF-κBp65-deficient (p65IEC-KO) mice compared to the control group.1 STAT3 is a crucial transcription factor involved in the response to oxidative stress, and its primary active form is phosphorylated STAT3, which plays a significant role in ferroptosis. Research conducted on colorectal cancer (CRC) has revealed a substantial expression of STAT3 in CRC tissues. Moreover, propofol can down-regulate STAT3, enhancing ferroptosis in CRC cells.10 Meanwhile, STAT3 is closely linked with ferroptosis in UC and could potentially serve as a novel therapeutic target.11 Mechanistic studies have also unveiled that myeloid FTH1 regulates both colitis and colitis-associated CRC through divalent metal transporter 1 (DMT1)-iron-STAT3 signaling pathway.11 Other regulators and ferroptosis in IBD: Notably, new regulators associated with ferroptosis in IBD are being explored. Recent research has unveiled the pivotal role of solute carrier family 6 member 14 (SLC6A14) in IBD-associated ferroptosis. Specifically, SLC6A14 augments the occurrence of ferroptosis in UC by repressing P21 (RAC1)-activated kinase 6 (PAK6) expression through CCAAT enhancer binding protein beta (C/EBPβ).12 Additionally, acyl CoA synthetase family member 2 (ACSF2) may serve as a promising target for ferroptosis in patients with IBD.13 Meanwhile, several antioxidants and anti-inflammatory substances have been reported to influence the outcome of experimental colitis by regulating intricate process of ferroptosis. For instance, liquiritin, a flavonoid component found in licorice, significantly contributed to colitis remission by activating peroxiredoxin-6 (Prdx6). This promotes the expression of ferritin and reduces cellular iron levels, inhibiting ferroptosis in IEC.14 Moreover, β-caryophyllene (BCP), a natural food flavor present in various plant essential oils, ameliorates experimental colitis by activating the type 2 cannabinoid receptor (CB2R) and suppressing macrophage ferroptosis.15 Gut microbial metabolites and ferroptosis: Gut microbial metabolites are essential factors in the pathological progression of IBD. However, further investigation is imperative to elucidate their specific mechanism of action in IBD. Previous studies have demonstrated the significant regulatory role of gut microbial metabolites in cell death Supplementary Table 2, https://links.lww.com/CM9/B954, including apoptosis, autophagy, pyroptosis, and necroptosis. Nevertheless, there is still a lack of research linking gut microbiota to ferroptosis. A recent study suggests that the supplementation of omega-3 polyunsaturated fatty acids (N-3PUFAs) and butyric acid can augment mitochondrial calcium levels and GPX4-dependent ferroptosis. This provides a valuable reference for establishing a connection between gut microbiota and ferroptosis.16 The butyrate was reported to induce ferroptosis in CRC cells through the CD44/SLC7A11 signaling pathway. The significance of intestinal microbial metabolites in regulating ferroptosis in IBD is therefore profound.17 The understanding of ferroptosis in the development and pathogenesis of IBD made significant progress in recent years. Further exploration is needed to ascertain whether specific regulatory agents or signaling pathways are directly associated with ferroptosis in IBD. The key discoveries regarding ferroptosis in IBD and the relationship between gut microbes and ferroptosis highlight the potential of targeting ferroptosis as a therapeutic approach. Summarizing the complex mechanism of ferroptosis, analyzing the impact of transcription factors on IBD-associated ferroptosis, outlining novel regulatory factors that target ferroptosis in IBD, and discussing the effect of intestinal flora metabolites on IBD ferroptosis can help us identify the challenges that need to be overcome when targeting ferroptosis for treating IBD. There are still many challenges that need to be overcome in targeting ferroptosis for the treatment of IBD. First, although the involvement of specific transcription factors in mediating ferroptosis in IBD has been established, the precise underlying mechanism remains unexplored. Meanwhile, there is considerable uncertainty surrounding other transcription factors that play a pivotal role in regulating ferroptosis. Second, many compounds have been tested to affect IBD based on identified ferroptosis targets. However, there is a lack of studies on the combination of existing therapeutic drugs and ferroptosis regulators for IBD. Finally, although the relationship between intestinal flora metabolites and ferroptosis has been studied, there is still a lack of relevant studies on how intestinal flora metabolites regulate IBD through ferroptosis intervention. In conclusion, we infer that ferroptosis involvement in IBD is uncertain and requires further investigation. Further elucidation of the ferroptosis pathway and the specific examination of the effect of different ferroptosis regulators in IBD are required. This could provide potential clues for ferroptosis-based IBD treatment. Funding This work was supported by grants from the National Natural Science Foundation of China (Nos. 82270565 and 82100565) and the Scientific research project of Tianjin Municipal Commission of Education (No. 2022KJ243). Conflicts of interest None.