Role of ferroptosis in the pathogenesis and as a therapeutic target of inflammatory bowel disease (Review)

Ocansey,Dickson Kofi Wiredu; Yuan,Jintao; Wei,Zhiping; Mao,Fei; Zhang,Zhaoyang

doi:10.3892/ijmm.2023.5256

Role of ferroptosis in the pathogenesis and as a therapeutic target of inflammatory bowel disease (Review)

Authors:
- Dickson Kofi Wiredu Ocansey
- Jintao Yuan
- Zhiping Wei
- Fei Mao
- Zhaoyang Zhang
View Affiliations

Affiliations: Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, School of Materials Science and Engineering, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China, The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang, Jiangsu 212300, P.R. China, Clinical Laboratory, Taicang Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu 215400, P.R. China
Published online on: May 16, 2023 https://doi.org/10.3892/ijmm.2023.5256
Article Number: 53
Copyright: © Ocansey et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Ferroptosis, a novel form of regulated cell death, is characterized by the accumulation of labile iron and lipid peroxidation, and the excessive production of reactive oxygen species (ROS). Although ferroptosis lies at the center of crucial biological activities involving O2, iron and polyunsaturated fatty acids (PUFAs), which are essential for cell proliferation and growth, the interaction between these molecules could also mediate the accumulation of toxic levels of ROS and lipid peroxides, which can then cause damage to cellular membranes and ultimately result in cell death. Recent reports have indicated that ferroptosis participates in the development and progression of inflammatory bowel disease (IBD), offering a new exploratory field which may aid in the more in‑depth understanding of the pathogenesis and therapeutic targets of IBD. Of note, the mitigation of the characteristic features of ferroptosis, such as depleted glutathione (GSH) levels, inactivated glutathione peroxidase 4 (GPX4), elevated levels of lipid peroxidation and iron overload significantly relieve IBD. This has attracted the attention of researches aiming to examine therapeutic agents that inhibit ferroptosis in IBD, including radical‑trapping antioxidants, enzyme inhibitors, iron chelators, protein degradation inhibitors, stem cell‑derived exosomes and oral N‑acetylcysteine or glutathione. The present review summarizes and discusses the current data that implicate ferroptosis in the pathogenesis of IBD and its inhibition as a novel alternate therapeutic target for IBD. The mechanisms and key mediators of ferroptosis, including GSH/GPX4, PUFAs, iron and organic peroxides are also discussed. Although the field is relatively new, the therapeutic regulation of ferroptosis has exhibited promising outcomes as a novel treatment avenue for IBD.

View Figures

View References

1	Hodson R: Inflammatory bowel disease. Nature. 540:S972016. View Article : Google Scholar : PubMed/NCBI
2	Cai Z, Wang S and Li J: Treatment of inflammatory bowel disease: A comprehensive review. Front Med. 8:7654742021. View Article : Google Scholar
3	Na SY and Moon W: Perspectives on current and novel treatments for inflammatory bowel disease. Gut Liver. 13:604–616. 2019. View Article : Google Scholar : PubMed/NCBI
4	Ocansey DKW, Xu X, Zhang L and Mao F: Mesenchymal stem cell-derived exosome: The likely game-changer in stem cell research. BIOCELL. 46:1169–1172. 2022. View Article : Google Scholar
5	Xu M, Tao J, Yang Y, Tan S, Liu H, Jiang J, Zheng F and Wu B: Ferroptosis involves in intestinal epithelial cell death in ulcerative colitis. Cell Death Dis. 11:862020. View Article : Google Scholar : PubMed/NCBI
6	Xu S, He Y, Lin L, Chen P, Chen M and Zhang S: The emerging role of ferroptosis in intestinal disease. Cell Death Dis. 12:2892021. View Article : Google Scholar : PubMed/NCBI
7	Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, et al: Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 149:1060–1072. 2012. View Article : Google Scholar : PubMed/NCBI
8	Otasevic V, Vucetic M, Grigorov I, Martinovic V and Stancic A: Ferroptosis in different pathological contexts seen through the eyes of mitochondria. Oxid Med Cell Longev. 2021:55373302021. View Article : Google Scholar : PubMed/NCBI
9	Battaglia AM, Chirillo R, Aversa I, Sacco A, Costanzo F and Biamonte F: Ferroptosis and cancer: Mitochondria meet the 'iron maiden' cell death. Cells. 9:15052020. View Article : Google Scholar
10	Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, Kang R and Tang D: Ferroptosis: Process and function. Cell Death Differ. 23:369–379. 2016. View Article : Google Scholar : PubMed/NCBI
11	Xu C, Liu Z and Xiao J: Ferroptosis: A double-edged sword in gastrointestinal disease. Int J Mol Sci. 22:124032021. View Article : Google Scholar : PubMed/NCBI
12	Gao W, Zhang T and Wu H: Emerging pathological engagement of ferroptosis in gut diseases. Oxid Med Cell Longev. 2021:42462552021. View Article : Google Scholar : PubMed/NCBI
13	Dixon SJ and Stockwell BR: The hallmarks of ferroptosis. Annu Rev Cancer Biol. 3:35–54. 2019. View Article : Google Scholar
14	Sui X, Zhang R, Liu S, Duan T, Zhai L, Zhang M, Han X, Xiang Y, Huang X, Lin H and Xie T: RSL3 drives ferroptosis through GPX4 inactivation and ROS production in colorectal cancer. Front Pharmacol. 9:13712018. View Article : Google Scholar : PubMed/NCBI
15	Huang J, Zhang J, Ma J, Ma J, Liu J, Wang F and Tang X: Inhibiting ferroptosis: A novel approach for ulcerative colitis therapeutics. Oxid Med Cell Longev. 2022:96786252022.PubMed/NCBI
16	Ma D, Jiang P, Jiang Y, Li H and Zhang D: Effects of lipid peroxidation-mediated ferroptosis on severe acute pancreatitis-induced intestinal barrier injury and bacterial translocation. Oxid Med Cell Longev. 2021:66445762021. View Article : Google Scholar : PubMed/NCBI
17	Xu J, Liu S, Cui Z, Wang X, Ning T, Wang T, Zhang N, Xie S, Min L, Zhang S, et al: Ferrostatin-1 alleviated TNBS induced colitis via the inhibition of ferroptosis. Biochem Biophys Res Commun. 573:48–54. 2021. View Article : Google Scholar : PubMed/NCBI
18	Wang S, Liu W, Wang J and Bai X: Curculigoside inhibits ferroptosis in ulcerative colitis through the induction of GPX4. Life Sci. 259:1183562020. View Article : Google Scholar : PubMed/NCBI
19	Huang F, Zhang S, Li X, Huang Y, He S and Luo L: STAT3-mediated ferroptosis is involved in ulcerative colitis. Free Radic Biol Med. 188:375–385. 2022. View Article : Google Scholar : PubMed/NCBI
20	Cao JY and Dixon SJ: Mechanisms of ferroptosis. Cell Mol Life Sci. 73:2195–2209. 2016. View Article : Google Scholar : PubMed/NCBI
21	Tang D, Chen X, Kang R and Kroemer G: Ferroptosis: Molecular mechanisms and health implications. Cell Res. 31:107–125. 2021. View Article : Google Scholar :
22	Jiang X, Stockwell BR and Conrad M: Ferroptosis: Mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 22:266–282. 2021. View Article : Google Scholar : PubMed/NCBI
23	Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, et al: Regulation of ferroptotic cancer cell death by GPX4. Cell. 156:317–331. 2014. View Article : Google Scholar : PubMed/NCBI
24	Hu W, Liang K, Zhu H, Zhao C, Hu H and Yin S: Ferroptosis and its role in chronic diseases. Cells. 11:20402022. View Article : Google Scholar : PubMed/NCBI
25	Conrad M and Pratt DA: The chemical basis of ferroptosis. Nat Chem Biol. 15:1137–1147. 2019. View Article : Google Scholar : PubMed/NCBI
26	Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, Superti-Furga G and Stockwell BR: Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol. 10:1604–1609. 2015. View Article : Google Scholar : PubMed/NCBI
27	Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, Irmler M, Beckers J, Aichler M, Walch A, et al: ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 13:91–98. 2017. View Article : Google Scholar :
28	Bano I, Horky P, Abbas SQ, Majid M, Bilal AHM, Ali F, Behl T, Hassan SSU and Bungau S: Ferroptosis: A new road towards cancer management. Molecules. 27:21292022. View Article : Google Scholar : PubMed/NCBI
29	Ursini F, Maiorino M and Gregolin C: The selenoenzyme phospholipid hydroperoxide glutathione peroxidase. Biochim Biophys Acta. 839:62–70. 1985. View Article : Google Scholar : PubMed/NCBI
30	Skouta R, Dixon SJ, Wang J, Dunn DE, Orman M, Shimada K, Rosenberg PA, Lo DC, Weinberg JM, Linkermann A and Stockwell BR: Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc. 136:4551–4556. 2014. View Article : Google Scholar : PubMed/NCBI
31	Chen X, Yu C, Kang R and Tang D: Iron metabolism in ferroptosis. Front Cell Dev Biol. 8:5902262020. View Article : Google Scholar : PubMed/NCBI
32	Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ III, Kang R and Tang D: Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 12:1425–1428. 2016. View Article : Google Scholar : PubMed/NCBI
33	Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB and Jiang X: Role of mitochondria in ferroptosis. Mol Cell. 73:354–363.e3. 2019. View Article : Google Scholar :
34	Gao M, Monian P, Pan Q, Zhang W, Xiang J and Jiang X: Ferroptosis is an autophagic cell death process. Cell Res. 26:1021–1032. 2016. View Article : Google Scholar : PubMed/NCBI
35	Chen X, Kang R, Kroemer G and Tang D: Organelle-specific regulation of ferroptosis. Cell Death Differ. 28:2843–2856. 2021. View Article : Google Scholar : PubMed/NCBI
36	Lee H, Zandkarimi F, Zhang Y, Meena JK, Kim J, Zhuang L, Tyagi S, Ma L, Westbrook TF, Steinberg GR, et al: Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat Cell Biol. 22:225–234. 2020. View Article : Google Scholar : PubMed/NCBI
37	Zhou H, Zhou YL, Mao JA, Tang LF, Xu J, Wang ZX, He Y and Li M: NCOA4-mediated ferritinophagy is involved in ionizing radiation-induced ferroptosis of intestinal epithelial cells. Redox Biol. 55:1024132022.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
38	Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS and Stockwell BR: Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA. 113:E4966–E4975. 2016. View Article : Google Scholar : PubMed/NCBI
39	Kobayashi Y, Ohfuji S, Kondo K, Fukushima W, Sasaki S, Kamata N, Yamagami H, Fujiwara Y, Suzuki Y and Hirota Y; Japanese Case-Control Study Group for Ulcerative Colitis: Association of dietary fatty acid intake with the development of ulcerative colitis: A multicenter case-control study in Japan. Inflamm Bowel Dis. 27:617–628. 2021. View Article : Google Scholar
40	John S, Luben R, Shrestha SS, Welch A, Khaw KT and Hart AR: Dietary n-3 polyunsaturated fatty acids and the aetiology of ulcerative colitis: A UK prospective cohort study. Eur J Gastroenterol Hepatol. 22:602–606. 2010. View Article : Google Scholar : PubMed/NCBI
41	Lee JY, Nam M, Son HY, Hyun K, Jang SY, Kim JW, Kim MW, Jung Y, Jang E, Yoon SJ, et al: Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer. Proc Natl Acad Sci USA. 117:32433–32442. 2020. View Article : Google Scholar : PubMed/NCBI
42	Ursini F and Maiorino M: Lipid peroxidation and ferroptosis: The role of GSH and GPx4. Free. Radic Biol Med. 152:175–185. 2020. View Article : Google Scholar
43	Chen X, Li J, Kang R, Klionsky DJ and Tang D: Ferroptosis: Machinery and regulation. Autophagy. 17:2054–2081. 2021. View Article : Google Scholar :
44	Conrad M and Sato H: The oxidative stress-inducible cystine/glutamate antiporter, system x (c) (-): Cystine supplier and beyond. Amino Acids. 42:231–246. 2012. View Article : Google Scholar
45	Ahmed I, Manno FAM, Manno SHC, Liu Y, Zhang Y and Lau C: Detection of lithium in breast milk and in situ elemental analysis of the mammary gland. Biomed Opt Express. 9:4184–4195. 2018. View Article : Google Scholar :
46	Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, Roveri A, Peng X, Porto Freitas F, Seibt T, et al: Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell. 172:409–422.e21. 2018. View Article : Google Scholar : PubMed/NCBI
47	Li S, He Y, Chen K, Sun J, Zhang L, He Y, Yu H and Li Q: RSL3 Drives ferroptosis through NF-κB pathway activation and GPX4 depletion in glioblastoma. Oxid Med Cell Longev. 2021:29150192021. View Article : Google Scholar
48	Zhang DL, Ghosh MC and Rouault TA: The physiological functions of iron regulatory proteins in iron homeostasis-an update. Front Pharmacol. 5:1242014. View Article : Google Scholar
49	Yang L, Cao LM, Zhang XJ and Chu B: Targeting ferroptosis as a vulnerability in pulmonary diseases. Cell Death Dis. 13:6492022. View Article : Google Scholar : PubMed/NCBI
50	Brown CW, Amante JJ, Chhoy P, Elaimy AL, Liu H, Zhu LJ, Baer CE, Dixon SJ and Mercurio AM: Prominin2 drives ferroptosis resistance by stimulating iron export. Dev Cell. 51:575–586.e4. 2019. View Article : Google Scholar : PubMed/NCBI
51	Kobayashi Y, Ohfuji S, Kondo K, Fukushima W, Sasaki S, Kamata N, Yamagami H, Fujiwara Y, Suzuki Y and Hirota Y; Japanese Case-Control Study Group for Ulcerative Colitis: Association between dietary iron and zinc intake and development of ulcerative colitis: A case-control study in Japan. J Gastroenterol Hepatol. 34:1703–1710. 2019. View Article : Google Scholar : PubMed/NCBI
52	Sivaprakasam S, Ristic B, Mudaliar N, Hamood AN, Colmer-Hamood J, Wachtel MS, Nevels AG, Kottapalli KR and Ganapathy V: Hereditary hemochromatosis promotes colitis and colon cancer and causes bacterial dysbiosis in mice. Biochem J. 477:3867–3883. 2020. View Article : Google Scholar : PubMed/NCBI
53	Wenz C, Faust D, Linz B, Turmann C, Nikolova T, Bertin J, Gough P, Wipf P, Schröder AS, Krautwald S and Dietrich C: t-BuOOH induces ferroptosis in human and murine cell lines. Arch Toxicol. 92:759–775. 2018. View Article : Google Scholar
54	Wenz C, Faust D, Linz B, Turmann C, Nikolova T and Dietrich C: Cell-cell contacts protect against t-BuOOH-induced cellular damage and ferroptosis in vitro. Arch Toxicol. 93:1265–1279. 2019. View Article : Google Scholar : PubMed/NCBI
55	Chen X, Kang R, Kroemer G and Tang D: Broadening horizons: The role of ferroptosis in cancer. Nat Rev Clin Oncol. 18:280–296. 2021. View Article : Google Scholar : PubMed/NCBI
56	Chen GQ, Benthani FA, Wu J, Liang D, Bian ZX and Jiang X: Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis. Cell Death Differ. 27:242–254. 2020. View Article : Google Scholar :
57	Gaschler MM, Andia AA, Liu H, Csuka JM, Hurlocker B, Vaiana CA, Heindel DW, Zuckerman DS, Bos PH, Reznik E, et al: FINO₂ initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol. 14:507–515. 2018. View Article : Google Scholar : PubMed/NCBI
58	Chen Y, Zhang P, Chen W and Chen G: Ferroptosis mediated DSS-induced ulcerative colitis associated with Nrf2/HO-1 signaling pathway. Immunol Lett. 225:9–15. 2020. View Article : Google Scholar : PubMed/NCBI
59	Hu Y, Sun S and Li H: Identification and functional exploration of Ferroptosis and Immune Related Long Non-Coding RNA in Inflammatory bowel disease. Res Sq. 2022.
60	Patankar JV and Becker C: Cell death in the gut epithelium and implications for chronic inflammation. Nat Rev Gastroenterol Hepatol. 17:543–556. 2020. View Article : Google Scholar : PubMed/NCBI
61	Luo L, Zhang S, Guo N, Li H and He S: ACSF2-mediated ferroptosis is involved in ulcerative colitis. Life Sci. 313:1212722023. View Article : Google Scholar
62	Cui DJ, Chen C, Yuan WQ, Yang YH and Han L: Integrative analysis of ferroptosis-related genes in ulcerative colitis. J Int Med Res. 49:30006052110429752021. View Article : Google Scholar : PubMed/NCBI
63	Ma H, Shu Q, Li D, Wang T, Li L, Song X, Lou K and Xu H: Accumulation of intracellular ferrous iron in inflammatory-activated macrophages. Biol Trace Elem Res. 201:2303–2310. 2023. View Article : Google Scholar
64	Maloy KJ and Powrie F: Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 474:298–306. 2011. View Article : Google Scholar : PubMed/NCBI
65	Panda SK, Peng V, Sudan R, Ulezko Antonova A, Di Luccia B, Ohara TE, Fachi JL, Grajales-Reyes GE, Jaeger N, Trsan T, et al: Repression of the aryl-hydrocarbon receptor prevents oxidative stress and ferroptosis of intestinal intraepithelial lymphocytes. Immunity. 56:797–812.e4. 2023. View Article : Google Scholar : PubMed/NCBI
66	Wang L, Han R, Zang K, Yuan P and Qin H: Deficiency in glutathione synthesis and reduction contributes to the pathogenesis of colitis-related liver injury. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 47:271–279. 2022.In English, Chinese. PubMed/NCBI
67	Lin JH, Walter P and Yen TSB: Endoplasmic reticulum stress in disease pathogenesis. Annu Rev Pathol. 3:399–425. 2008. View Article : Google Scholar
68	Li Y, Feng D, Wang Z, Zhao Y, Sun R, Tian D, Liu D, Zhang F, Ning S, Yao J and Tian X: Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ. 26:2284–2299. 2019. View Article : Google Scholar : PubMed/NCBI
69	Dang D, Zhang C, Meng Z, Lv X, Li Z, Wei J and Wu H: Integrative analysis links ferroptosis to necrotizing enterocolitis and reveals the role of ACSL4 in immune disorders. iScience. 25:1054062022. View Article : Google Scholar : PubMed/NCBI
70	Zhang X, Li W, Ma Y, Zhao X, He L, Sun P and Wang H: High-fat diet aggravates colitis-associated carcinogenesis by evading ferroptosis in the ER stress-mediated pathway. Free Radic Biol Med. 177:156–166. 2021. View Article : Google Scholar : PubMed/NCBI
71	Chen J, Li X, Ge C, Min J and Wang F: The multifaceted role of ferroptosis in liver disease. Cell Death Differ. 29:467–480. 2022. View Article : Google Scholar : PubMed/NCBI
72	Zhang X, Du L, Qiao Y, Zhang X, Zheng W, Wu Q, Chen Y, Zhu G, Liu Y, Bian Z, et al: Ferroptosis is governed by differential regulation of transcription in liver cancer. Redox Biol. 24:1012112019. View Article : Google Scholar : PubMed/NCBI
73	Wang Y, Zhang Z, Sun W, Zhang J, Xu Q, Zhou X and Mao L: Ferroptosis in colorectal cancer: Potential mechanisms and effective therapeutic targets. Biomed Pharmacother. 153:1135242022. View Article : Google Scholar : PubMed/NCBI
74	Ouyang S, Li H, Lou L, Huang Q, Zhang Z, Mo J, Li M, Lu J, Zhu K, Chu Y, et al: Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer. Redox Biol. 52:1023172022. View Article : Google Scholar : PubMed/NCBI
75	Xu T, Ding W, Ji X, Ao X, Liu Y, Yu W and Wang J: Molecular mechanisms of ferroptosis and its role in cancer therapy. J Cell Mol Med. 23:4900–4912. 2019. View Article : Google Scholar : PubMed/NCBI
76	Wang R, Su Q, Yin H, Wu D, Lv C and Yan Z: Inhibition of SRSF9 enhances the sensitivity of colorectal cancer to erastin-induced ferroptosis by reducing glutathione peroxidase 4 expression. Int J Biochem Cell Biol. 134:1059482021. View Article : Google Scholar : PubMed/NCBI
77	Zhang L, Liu W, Liu F, Wang Q, Song M, Yu Q, Tang K, Teng T, Wu D, Wang X, et al: Corrigendum to 'IMCA induces ferroptosis mediated by SLC7A11 through the AMPK/mTOR pathway in colorectal cancer'. Oxid Med Cell Longev. 2020:69014722020. View Article : Google Scholar
78	Xia Y, Liu S, Li C, Ai Z, Shen W, Ren W and Yang X: Discovery of a novel ferroptosis inducer-talaroconvolutin A-killing colorectal cancer cells in vitro and in vivo. Cell Death Dis. 11:9882020. View Article : Google Scholar : PubMed/NCBI
79	Gao W, Huang Z, Duan J, Nice EC, Lin J and Huang C: Elesclomol induces copper-dependent ferroptosis in colorectal cancer cells via degradation of ATP7A. Mol Oncol. 15:3527–3544. 2021. View Article : Google Scholar : PubMed/NCBI
80	Luo W, Dai W, Li Q, Mo S, Han L, Xiao X, Gu R, Xiang W, Ye L, Wang R, et al: Ferroptosis-associated molecular classification characterized by distinct tumor microenvironment profiles in colorectal cancer. Int J Biol Sci. 18:1773–1794. 2022. View Article : Google Scholar : PubMed/NCBI
81	Zilka O, Shah R, Li B, Friedmann Angeli JP, Griesser M, Conrad M and Pratt DA: On the mechanism of cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death. ACS Cent Sci. 3:232–243. 2017. View Article : Google Scholar : PubMed/NCBI
82	Kajarabille N and Latunde-Dada GO: Programmed cell-death by ferroptosis: Antioxidants as mitigators. Int J Mol Sci. 20:49682019. View Article : Google Scholar : PubMed/NCBI
83	Chen Y, Yan W, Chen Y, Zhu J, Wang J, Jin H, Wu H, Zhang G, Zhan S, Xi Q, et al: SLC6A14 facilitates epithelial cell ferroptosis via the C/EBPβ-PAK6 axis in ulcerative colitis. Cell Mol Life Sci. 79:5632022. View Article : Google Scholar
84	Hu Q, Zhang Y, Lou H, Ou Z, Liu J, Duan W, Wang H, Ge Y, Min J, Wang F and Ju Z: GPX4 and vitamin E cooperatively protect hematopoietic stem and progenitor cells from lipid peroxidation and ferroptosis. Cell Death Dis. 12:7062021. View Article : Google Scholar : PubMed/NCBI
85	Maiorino M, Conrad M and Ursini F: GPx4, lipid peroxidation, and cell death: Discoveries, rediscoveries, and open issues. Antioxid Redox Signal. 29:61–74. 2018. View Article : Google Scholar
86	Carlson BA, Tobe R, Yefremova E, Tsuji PA, Hoffmann VJ, Schweizer U, Gladyshev VN, Hatfield DL and Conrad M: Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration. Redox Biol. 9:22–31. 2016. View Article : Google Scholar : PubMed/NCBI
87	Mirbagheri SA, Nezami BG, Assa S and Hajimahmoodi M: Rectal administration of d-alpha tocopherol for active ulcerative colitis: A preliminary report. World J Gastroenterol. 14:5990–5995. 2008. View Article : Google Scholar : PubMed/NCBI
88	Rachmawati H, Pradana AT, Safitri D and Adnyana IK: Multiple functions of D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) as curcumin nanoparticle stabilizer: In vivo kinetic profile and anti-ulcerative colitis analysis in animal model. Pharmaceutics. 9:242017. View Article : Google Scholar
89	Liu KY, Nakatsu CH, Jones-Hall Y, Kozik A and Jiang Q: Vitamin E alpha- and gamma-tocopherol mitigate colitis, protect intestinal barrier function and modulate the gut microbiota in mice. Free Radic Biol Med. 163:180–189. 2021. View Article : Google Scholar
90	Wang Y, Shen W, Shi X, Fu F, Fan Y, Shen W, Cao Y, Zhang Q and Qi R: Alpha-tocopheryl succinate-conjugated G5 PAMAM dendrimer enables effective inhibition of ulcerative colitis. Adv Healthc Mater. 6:2017. View Article : Google Scholar
91	Zou Y, Li H, Graham ET, Deik AA, Eaton JK, Wang W, Sandoval-Gomez G, Clish CB, Doench JG and Schreiber SL: Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat Chem Biol. 16:302–309. 2020. View Article : Google Scholar : PubMed/NCBI
92	Yao X, Zhang Y, Hao J, Duan HQ, Zhao CX, Sun C, Li B, Fan BY, Wang X, Li WX, et al: Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis. Neural Regen Res. 14:532–541. 2019. View Article : Google Scholar :
93	Guo Z, Lin J, Sun K, Guo J, Yao X, Wang G, Hou L, Xu J, Guo J and Guo F: Deferoxamine alleviates osteoarthritis by inhibiting chondrocyte ferroptosis and activating the Nrf2 pathway. Front Pharmacol. 13:7913762022. View Article : Google Scholar : PubMed/NCBI
94	Ma H, Wang X, Zhang W, Li H, Zhao W, Sun J and Yang M: Melatonin suppresses ferroptosis induced by high glucose via activation of the Nrf2/HO-1 signaling pathway in type 2 diabetic osteoporosis. Oxid Med Cell Longev. 2020:90676102020. View Article : Google Scholar : PubMed/NCBI
95	Bai T, Li M, Liu Y, Qiao Z and Wang Z: Inhibition of ferroptosis alleviates atherosclerosis through attenuating lipid peroxidation and endothelial dysfunction in mouse aortic endothelial cell. Free Radic Biol Med. 160:92–102. 2020. View Article : Google Scholar : PubMed/NCBI
96	Rayatpour A, Foolad F, Heibatollahi M, Khajeh K and Javan M: Ferroptosis inhibition by deferiprone, attenuates myelin damage and promotes neuroprotection in demyelinated optic nerve. Sci Rep. 12:196302022. View Article : Google Scholar : PubMed/NCBI
97	Liu X, Zhang J and Xie W: The role of ferroptosis in acute lung injury. Mol Cell Biochem. 477:1453–1461. 2022. View Article : Google Scholar : PubMed/NCBI
98	Millar AD, Rampton DS and Blake DR: Effects of iron and iron chelation in vitro on mucosal oxidant activity in ulcerative colitis. Aliment Pharmacol Ther. 14:1163–1168. 2000. View Article : Google Scholar : PubMed/NCBI
99	Minaiyan M, Mostaghel E and Mahzouni P: Preventive therapy of experimental colitis with selected iron chelators and anti-oxidants. Int J Prev Med. 3(Suppl 1): S162–S169. 2012.PubMed/NCBI
100	Wu Y, Ran L, Yang Y, Gao X, Peng M, Liu S, Sun L, Wan J, Wang Y, Yang K, et al: Deferasirox alleviates DSS-induced ulcerative colitis in mice by inhibiting ferroptosis and improving intestinal microbiota. Life Sci. 314:1213122023. View Article : Google Scholar
101	Ghaith MM, El-Boshy M, Almasmoum H, Abdelghany AH, Azzeh FS, Almaimani RA, Idris S, Ahmad J, Mahbub AA, BaSalamah MA, et al: Deferasirox and vitamin D₃ co-therapy mitigates iron-induced renal injury by enhanced modulation of cellular anti-inflammatory, anti-oxidative stress, and iron regulatory pathways in rat. J Trace Elem Med Biol. 74:1270852022. View Article : Google Scholar
102	Chen X, Comish PB, Tang D and Kang R: Characteristics and biomarkers of ferroptosis. Front Cell Dev Biol. 9:6371622021. View Article : Google Scholar : PubMed/NCBI
103	Li YY, Wang XJ, Su YL, Wang Q, Huang SW, Pan ZF, Chen YP, Liang JJ, Zhang ML, Xie XQ, et al: Baicalein ameliorates ulcerative colitis by improving intestinal epithelial barrier via AhR/IL-22 pathway in ILC3s. Acta Pharmacol Sin. 43:1495–1507. 2022. View Article : Google Scholar
104	Thermozier S, Hou W, Zhang X, Shields D, Fisher R, Bayir H, Kagan V, Yu J, Liu B, Bahar I, et al: Anti-ferroptosis drug enhances total-body irradiation mitigation by drugs that block apoptosis and necroptosis. Radiat Res. 193:435–450. 2020. View Article : Google Scholar : PubMed/NCBI
105	Gounaris E, Heiferman MJ, Heiferman JR, Shrivastav M, Vitello D, Blatner NR, Knab LM, Phillips JD, Cheon EC, Grippo PJ, et al: Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation. PLoS One. 10:e01214022015. View Article : Google Scholar : PubMed/NCBI
106	Dächert J, Ehrenfeld V, Habermann K, Dolgikh N and Fulda S: Targeting ferroptosis in rhabdomyosarcoma cells. Int J Cancer. 146:510–520. 2020. View Article : Google Scholar
107	Shimada K, Skouta R, Kaplan A, Yang WS, Hayano M, Dixon SJ, Brown LM, Valenzuela CA, Wolpaw AJ and Stockwell BR: Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol. 12:497–503. 2016. View Article : Google Scholar : PubMed/NCBI
108	Wang D, Peng Y, Xie Y, Zhou B, Sun X, Kang R and Tang D: Antiferroptotic activity of non-oxidative dopamine. Biochem Biophys Res Commun. 480:602–607. 2016. View Article : Google Scholar : PubMed/NCBI
109	Liu L, Wu Y, Wang B, Jiang Y, Lin L, Li X and Yang S: DA-DRD5 signaling controls colitis by regulating colonic M1/M2 macrophage polarization. Cell Death Dis. 12:5002021. View Article : Google Scholar : PubMed/NCBI
110	Kawano M, Saika K, Takagi R, Matsui M and Matsushita S: Tannic acid acts as an agonist of the dopamine D2L receptor, regulates immune responses, and ameliorates experimentally induced colitis in mice. Brain Behav Immun Health. 5:1000712020. View Article : Google Scholar : PubMed/NCBI
111	Wu Z, Geng Y, Lu X, Shi Y, Wu G, Zhang M, Shan B, Pan H and Yuan J: Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc Natl Acad Sci USA. 116:2996–3005. 2019. View Article : Google Scholar : PubMed/NCBI
112	Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, Dignass A, Nachury M, Ferrante M, Kazemi-Shirazi L, et al: Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: A phase 3 randomised, double-blind controlled trial. Lancet. 388:1281–1290. 2016. View Article : Google Scholar : PubMed/NCBI
113	Ocansey DKW, Pei B, Yan Y, Qian H, Zhang X, Xu W and Mao F: Improved therapeutics of modified mesenchymal stem cells: An update. J Transl Med. 18:422020. View Article : Google Scholar : PubMed/NCBI
114	Ocansey DKW, Qiu W, Wang J, Yan Y, Qian H, Zhang X, Xu W and Mao F: The achievements and challenges of mesenchymal stem cell-based therapy in inflammatory bowel disease and its associated colorectal cancer. Stem Cells Int. 2020:78198242020. View Article : Google Scholar : PubMed/NCBI
115	Ocansey DKW, Zhang Z, Xu X, Liu L, Amoah S, Chen X, Wang B, Zhang X and Mao F: Mesenchymal stem cell-derived exosome mitigates colitis via the modulation of the gut metagenomics-metabolomics-farnesoid X receptor axis. Biomater Sci. 10:4822–4836. 2022. View Article : Google Scholar : PubMed/NCBI
116	Wang G, Joel MDM, Yuan J, Wang J, Cai X, Ocansey DKW, Yan Y, Qian H, Zhang X, Xu W and Mao F: Human umbilical cord mesenchymal stem cells alleviate inflammatory bowel disease by inhibiting ERK phosphorylation in neutrophils. Inflammopharmacology. 28:603–616. 2020. View Article : Google Scholar : PubMed/NCBI
117	Ocansey DKW, Zhang L, Wang Y, Yan Y, Qian H, Zhang X, Xu W and Mao F: Exosome-mediated effects and applications in inflammatory bowel disease. Biol Rev Camb Philos Soc. 95:1287–1307. 2020. View Article : Google Scholar : PubMed/NCBI
118	Zhu Y, Qin H, Sun C, Shao B, Li G, Qin Y, Kong D, Ren S, Wang H, Wang Z, et al: Endometrial regenerative cell-derived exosomes attenuate experimental colitis through downregulation of intestine ferroptosis. Stem Cells Int. 2022:30141232022. View Article : Google Scholar : PubMed/NCBI
119	Lin F, Chen W, Zhou J, Zhu J, Yao Q, Feng B, Feng X, Shi X, Pan Q, Yu J, et al: Mesenchymal stem cells protect against ferroptosis via exosome-mediated stabilization of SLC7A11 in acute liver injury. Cell Death Dis. 13:2712022. View Article : Google Scholar : PubMed/NCBI
120	Liu T, Jiang L, Tavana O and Gu W: The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res. 79:1913–1924. 2019. View Article : Google Scholar : PubMed/NCBI
121	Shao C, Chen Y, Yang T, Zhao H and Li D: Mesenchymal stem cell derived exosomes suppress neuronal cell ferroptosis via lncGm36569/miR-5627-5p/FSP1 axis in acute spinal cord injury. Stem Cell Rev Rep. 18:1127–1142. 2022. View Article : Google Scholar : PubMed/NCBI
122	Sun Z, Wu J, Bi Q and Wang W: Exosomal lncRNA TUG1 derived from human urine-derived stem cells attenuates renal ischemia/reperfusion injury by interacting with SRSF1 to regulate ASCL4-mediated ferroptosis. Stem Cell Res Ther. 13:2972022. View Article : Google Scholar : PubMed/NCBI
123	Song Y, Wang B, Zhu X, Hu J, Sun J, Xuan J and Ge Z: Human umbilical cord blood-derived MSCs exosome attenuate myocardial injury by inhibiting ferroptosis in acute myocardial infarction mice. Cell Biol Toxicol. 37:51–64. 2021. View Article : Google Scholar
124	Tan Y, Huang Y, Mei R, Mao F, Yang D, Liu J, Xu W, Qian H and Yan Y: HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis. Cell Death Dis. 13:3192022. View Article : Google Scholar : PubMed/NCBI
125	Atkuri KR, Mantovani JJ and Herzenberg LA and Herzenberg LA: N-acetylcysteine-a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. 7:355–359. 2007. View Article : Google Scholar : PubMed/NCBI
126	Schmitt B, Vicenzi M, Garrel C and Denis FM: Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study. Redox Biol. 6:198–205. 2015. View Article : Google Scholar : PubMed/NCBI
127	Ardite E, Sans M, Panés J, Romero FJ, Piqué JM and Fernández-Checa JC: Replenishment of glutathione levels improves mucosal function in experimental acute colitis. Lab Invest. 80:735–744. 2000. View Article : Google Scholar : PubMed/NCBI
128	Dong S, Lu Y, Peng G, Li J, Li W, Li M, Wang H, Liu L and Zhao Q: Furin inhibits epithelial cell injury and alleviates experimental colitis by activating the Nrf2-Gpx4 signaling pathway. Dig Liver Dis. 53:1276–1285. 2021. View Article : Google Scholar : PubMed/NCBI
129	Zhu D, Wu H, Jiang K, Xu Y, Miao Z, Wang H and Ma Y: Zero-valence selenium-enriched prussian blue nanozymes reconstruct intestinal barrier against inflammatory bowel disease via inhibiting ferroptosis and T cells differentiation. Adv Healthc Mater. 12:e22031602023. View Article : Google Scholar : PubMed/NCBI
130	Perry C, Kapur N and Barrett TA: DPP-4 as a novel biomarker for inflammatory bowel disease: Is it ready for clinical use? Inflamm Bowel Dis. 26:1720–1721. 2020. View Article : Google Scholar : PubMed/NCBI
131	Xie Y, Zhu S, Song X, Sun X, Fan Y, Liu J, Zhong M, Yuan H, Zhang L, Billiar TR, et al: The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep. 20:1692–1704. 2017. View Article : Google Scholar : PubMed/NCBI
132	Arab HH, Eid AH, Mahmoud AM and Senousy MA: Linagliptin mitigates experimental inflammatory bowel disease in rats by targeting inflammatory and redox signaling. Life Sci. 273:1192952021. View Article : Google Scholar : PubMed/NCBI
133	El-Ghannam MS, Saad MA, Nassar NN, El-Yamany MF and El-Bahy AAZ: Linagliptin ameliorates acetic acid-induced colitis via modulating AMPK/SIRT1/PGC-1α and JAK2/STAT3 signaling pathway in rats. Toxicol Appl Pharmacol. 438:1159062022. View Article : Google Scholar
134	Hu Y, Mao Z, Xu L, Yin L, Tao X, Tang Z, Qi Y, Sun P and Peng J: Protective effect of dioscin against intestinal ischemia/reperfusion injury via adjusting miR-351-5p-mediated oxidative stress. Pharmacol Res. 137:56–63. 2018. View Article : Google Scholar : PubMed/NCBI
135	Ozkan OV, Yuzbasioglu MF, Ciralik H, Kurutas EB, Yonden Z, Aydin M, Bulbuloglu E, Semerci E, Goksu M, Atli Y, et al: Resveratrol, a natural antioxidant, attenuates intestinal ischemia/reperfusion injury in rats. Tohoku J Exp Med. 218:251–258. 2009. View Article : Google Scholar : PubMed/NCBI
136	Stefanutti G, Pierro A, Parkinson EJ, Smith VV and Eaton S: Moderate hypothermia as a rescue therapy against intestinal ischemia and reperfusion injury in the rat. Crit Care Med. 36:1564–1572. 2008. View Article : Google Scholar : PubMed/NCBI
137	Meister AL, Doheny KK and Travagli RA: Necrotizing enterocolitis: It's not all in the gut. Exp Biol Med (Maywood). 245:85–95. 2020. View Article : Google Scholar
138	Yin Y, Wu X, Peng B, Zou H, Li S, Wang J and Cao J: Curcumin improves necrotising microscopic colitis and cell pyroptosis by activating SIRT1/NRF2 and inhibiting the TLR4 signalling pathway in newborn rats. Innate Immun. 26:609–617. 2020. View Article : Google Scholar : PubMed/NCBI
139	Xu Y, Li X, Cheng Y, Yang M and Wang R: Inhibition of ACSL4 attenuates ferroptotic damage after pulmonary ischemia-reperfusion. FASEB J. 34:16262–16275. 2020. View Article : Google Scholar : PubMed/NCBI
140	Cui Y, Zhang Y, Zhao X, Shao L, Liu G, Sun C, Xu R and Zhang Z: ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation. Brain Behav Immun. 93:312–321. 2021. View Article : Google Scholar : PubMed/NCBI
141	Zhang L, Fan J, He J, Chen W, Jin W, Zhu Y, Sun H, Li Y, Shi Y, Jing Y, et al: Regulation of ROS-NF-κB axis by tuna backbone derived peptide ameliorates inflammation in necrotizing enterocolitis. J Cell Physiol. 234:14330–14338. 2019. View Article : Google Scholar : PubMed/NCBI
142	Tang B, Zhu J, Fang S, Wang Y, Vinothkumar R, Li M, Weng Q, Zheng L, Yang Y, Qiu R, et al: Pharmacological inhibition of MELK restricts ferroptosis and the inflammatory response in colitis and colitis-propelled carcinogenesis. Free Radic Biol Med. 172:312–329. 2021. View Article : Google Scholar : PubMed/NCBI