{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T22:26:23Z","timestamp":1781043983917,"version":"3.54.1"},"reference-count":39,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China (NSFC)","award":["696"],"award-info":[{"award-number":["696"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Deoxynivalenol (DON), known as vomitoxin, is one of the most common mycotoxins produced by Fusarium graminearum, with high detection rates in feed worldwide. Ferroptosis is a novel mode of cell death characterized by lipid peroxidation and the accumulation of reactive oxygen species. Although it has been demonstrated that DON can induce ferroptosis in the liver, the specific mechanisms and pathways are still unknown. The aim of this experiment was to investigate that DON can induce iron metabolism disorders in the livers of mice, thereby triggering ferroptosis and causing toxic damage to the liver. Methods: Male C57 mice were treated with DON at a 5 mg\/kg BW concentration as an in vivo model. After sampling, organ coefficient monitoring, liver function test, histopathological analysis, liver Fe2+ content test, and oxidative stress-related indexes were performed. The mRNA and protein expression of Nrf2 and its downstream genes were also detected using a series of methods including quantitative real-time PCR, immunofluorescence double-labeling, and Western blotting analysis. Results: DON can cause damage to the liver of a mouse. Specifically, we found that mouse livers in the DON group exhibited pathological damage in cell necrosis, inflammatory infiltration, cytoplasmic vacuolization, elevated relative liver weight, and significant changes in liver function indexes. Meanwhile, the substantial reduction in the levels of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC) in the DON group indicated that DON also caused oxidative stress in the liver. Notably, DON exposure increased the levels of Fe2+ and Malondialdehyde (MDA) in the liver, which provides strong evidence for the occurrence of iron metabolism and ferroptosis disorders. Most importantly, mRNA and protein expression of Nrf2, an important pathway for iron metabolism and ferroptosis, along with its downstream genes, heme oxygenase (HO-1), quinone oxidoreductase (NQO1), glutathione peroxidase (GPX4), and solute carrier gene (SLC7a11), were significantly inhibited in the DON group. Conclusions: Based on our results, the Nrf2 pathway is closely associated with DON-induced iron metabolism disorders and ferroptosis in mouse livers, suggesting that maintaining hepatic iron homeostasis and activating the Nrf2 pathway may be a potential target for mitigating DON hepatotoxicity in the future.<\/jats:p>","DOI":"10.3390\/metabo15030165","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T03:22:44Z","timestamp":1740972164000},"page":"165","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Disorders of Iron Metabolism: A \u201cSharp Edge\u201d of Deoxynivalenol-Induced Hepatotoxicity"],"prefix":"10.3390","volume":"15","author":[{"given":"Haoyue","family":"Guan","sequence":"first","affiliation":[{"name":"Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujing","family":"Cui","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Hua","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youtian","family":"Deng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huidan","family":"Deng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junliang","family":"Deng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.fct.2005.08.021","article-title":"Fusariotoxin transfer in animal","volume":"44","author":"Cavret","year":"2006","journal-title":"Food Chem. Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.tifs.2018.11.003","article-title":"Food raw materials and food production occurrences of deoxynivalenol in different regions","volume":"83","author":"Wang","year":"2019","journal-title":"Trends Food Sci. Technol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.3390\/toxins4111120","article-title":"Advances in deoxynivalenol toxicity mechanisms: The brain as a target","volume":"4","author":"Bonnet","year":"2012","journal-title":"Toxins"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s00204-010-0579-8","article-title":"Deoxynivalenol: Mechanisms of action, human exposure, and toxicological relevance","volume":"84","author":"Pestka","year":"2010","journal-title":"Arch. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.toxicon.2016.04.036","article-title":"Anorexic action of deoxynivalenol in hypothalamus and intestine","volume":"118","author":"Tominaga","year":"2016","journal-title":"Toxicon"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.toxicon.2019.02.018","article-title":"Deoxynivalenol-induced oxidative stress and Nrf2 translocation in maternal liver on gestation day 12.5 d and 18.5 d","volume":"161","author":"Yu","year":"2019","journal-title":"Toxicon"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.toxlet.2018.07.007","article-title":"Response of intestinal HT-29 cells to the trichothecene mycotoxin deoxynivalenol and its sulfated conjugates","volume":"295","author":"Woelflingseder","year":"2018","journal-title":"Toxicol. Lett."},{"key":"ref_8","first-page":"373","article-title":"Hazard assessment of the health effects of deoxynivalenol","volume":"35","author":"Tong","year":"2021","journal-title":"J. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.aninu.2021.11.009","article-title":"Cytochrome P450 enzymes mediated by DNA methylation is involved in deoxynivalenol-induced hepatoxicity in piglets","volume":"9","author":"Liu","year":"2022","journal-title":"Anim. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1002\/jat.3428","article-title":"Current sights for mechanisms of deoxynivalenol-induced hepatotoxicity and prospective views for future scientific research: A mini review","volume":"37","author":"Peng","year":"2017","journal-title":"J. Appl. Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Liu, M., Zhang, L., Mo, Y., Li, J., Yang, J., Wang, J., Karrow, N.A., Wu, H., and Sun, L. (2023). Ferroptosis is involved in deoxynivalenol-induced intestinal damage in pigs. J. Anim. Sci. Biotechnol., 14.","DOI":"10.1186\/s40104-023-00841-4"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"113730","DOI":"10.1016\/j.fct.2023.113730","article-title":"Deoxynivalenol induces testicular ferroptosis by regulating the Nrf2\/System Xc\u2212\/GPX4 axis","volume":"175","author":"Yang","year":"2023","journal-title":"Food Chem. Toxicol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6660","DOI":"10.1021\/acs.jafc.4c00556","article-title":"Ferritinophagy is critical for deoxynivalenol-induced liver injury in mice","volume":"72","author":"Jiang","year":"2024","journal-title":"J. Agric. Food Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"153689","DOI":"10.1016\/j.tox.2023.153689","article-title":"Selenomethionine protects the liver from dietary deoxynivalenol exposure via Nrf2\/PPAR\u03b3-GPX4-ferroptosis pathway in mice","volume":"501","author":"Fan","year":"2024","journal-title":"Toxicology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"215.e1","DOI":"10.1016\/j.crad.2017.07.022","article-title":"Tissue iron quantification in chronic liver diseases using MRI shows a relationship between iron accumulation in liver, spleen, and bone marrow","volume":"73","author":"Porto","year":"2018","journal-title":"Clin. Radiol."},{"key":"ref_17","first-page":"2763","article-title":"Nrf2 regulates CD4+ T cell\u2013induced acute graft-versus-host disease in mice","volume":"132","author":"Tsai","year":"2018","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Dodson, M., Castro-Portuguez, R., and Zhang, D.D. (2019). NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol., 23.","DOI":"10.1016\/j.redox.2019.101107"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"113811","DOI":"10.1016\/j.ecoenv.2022.113811","article-title":"Dihydroartemisinin alleviates deoxynivalenol induced liver apoptosis and inflammation in piglets","volume":"241","author":"Li","year":"2022","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111140","DOI":"10.1016\/j.fct.2020.111140","article-title":"Comparative toxicokinetics of Fusarium mycotoxins in pigs and humans","volume":"137","author":"Schelstraete","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.3390\/ijms9112062","article-title":"Fumonisins, trichothecenes and zearalenone in cereals","volume":"9","author":"Yazar","year":"2008","journal-title":"Int. J. Mol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"772","DOI":"10.4315\/0362-028X-67.4.772","article-title":"Microbial loads, mycotoxins, and quality of durum wheat from the 2001 harvest of the northern plains region of the United States","volume":"67","author":"Manthey","year":"2004","journal-title":"J. Food Prot."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.toxlet.2014.12.017","article-title":"The food born mycotoxin deoxynivalenol induces low-grade inflammation in mice in the absence of observed-adverse effects","volume":"232","author":"Tardivel","year":"2015","journal-title":"Toxicol. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s00204-019-02649-6","article-title":"Heme oxygenase-1 regulates autophagy through carbon\u2013oxygen to alleviate deoxynivalenol-induced hepatic damage","volume":"94","author":"Peng","year":"2020","journal-title":"Arch. Toxicol."},{"key":"ref_25","unstructured":"Duncan, J., Prasse, K., and Mahaffey, E. (1994). Veterinary Laboratory Medicine: Clinical Pathology, Iowa State University Press."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.tox.2007.11.021","article-title":"The current state of serum biomarkers of hepatotoxicity","volume":"245","author":"Ozer","year":"2008","journal-title":"Toxicology"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Fan, W., Shen, T., Ding, Q., Lv, Y., Li, L., Huang, K., Yan, L., and Song, S. (2017). Zearalenone induces ROS-mediated mitochondrial damage in porcine IPEC-J2 cells. J. Biochem. Mol. Toxicol., 31.","DOI":"10.1002\/jbt.21944"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8182","DOI":"10.1021\/acs.jafc.3c01035","article-title":"Lactoferrin relieves Deoxynivalenol-induced oxidative stress and inflammatory response by modulating the Nrf2\/MAPK pathways in the liver","volume":"71","author":"Hu","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2621","DOI":"10.1080\/15548627.2023.2218764","article-title":"GPX4 in cell death, autophagy, and disease","volume":"19","author":"Xie","year":"2023","journal-title":"Autophagy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1080\/15548627.2020.1810918","article-title":"Ferroptosis: Machinery and regulation","volume":"17","author":"Chen","year":"2021","journal-title":"Autophagy"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.chembiol.2020.02.005","article-title":"Autophagy-dependent ferroptosis: Machinery and regulation","volume":"27","author":"Liu","year":"2020","journal-title":"Cell Chem. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.jff.2017.10.027","article-title":"Lycopene relieves AFB1-induced liver injury through enhancing hepatic antioxidation and detoxification potential with Nrf2 activation","volume":"39","author":"Xu","year":"2017","journal-title":"J. Funct. Foods"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Suraweera, T.L., Rupasinghe, H.V., Dellaire, G., and Xu, Z. (2020). Regulation of Nrf2\/ARE pathway by dietary flavonoids: A friend or foe for cancer management?. Antioxidants, 9.","DOI":"10.3390\/antiox9100973"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1002\/mnfr.201400381","article-title":"Antioxidative stress effect of phosphoserine dimers is mediated via activation of the Nrf2 signaling pathway","volume":"59","author":"Mine","year":"2015","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1007\/s12272-014-0380-y","article-title":"Involvement of Nrf2-GSH signaling in TGF\u03b21-stimulated epithelial-to-mesenchymal transition changes in rat renal tubular cells","volume":"38","author":"Ryoo","year":"2015","journal-title":"Arch. Pharmacal Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12950-019-0216-0","article-title":"Ferroptosis inhibitor alleviates Radiation-induced lung fibrosis (RILF) via down-regulation of TGF-\u03b21","volume":"16","author":"Li","year":"2019","journal-title":"J. Inflamm."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Dagallier, C., Avry, F., Touchefeu, Y., Buron, F., Routier, S., Ch\u00e9rel, M., and Arlicot, N. (2021). Development of PET radioligands targeting COX-2 for colorectal cancer staging, a review of in vitro and preclinical imaging studies. Front. Med., 8.","DOI":"10.3389\/fmed.2021.675209"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.cell.2013.12.010","article-title":"Regulation of ferroptotic cancer cell death by GPX4","volume":"156","author":"Yang","year":"2014","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s10020-024-00993-7","article-title":"Hyperoxia-activated Nrf2 regulates ferroptosis in intestinal epithelial cells and intervenes in inflammatory reaction through COX-2\/PGE2\/EP2 pathway","volume":"31","author":"Liu","year":"2025","journal-title":"Mol. Med."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/3\/165\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:45:21Z","timestamp":1760028321000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/3\/165"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,1]]},"references-count":39,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["metabo15030165"],"URL":"https:\/\/doi.org\/10.3390\/metabo15030165","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,1]]}}}