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The purpose of this paper was to investigate the possible mechanism of toxicity of IBC on HepG2 cells and zebrafish embryos. The results showed that exposure to IBC increased zebrafish embryo mortality and decreased hatchability. Meanwhile, IBC induced liver injury and increased expression of ALT and AST activity. Further studies showed that IBC caused the increase of ROS and MDA the decrease of CAT, GSH, and GSH\u2010Px; the increase of Fe<jats:sup>2+<\/jats:sup> content; and the changes of ferroptosis related genes (<jats:italic>acsl4<\/jats:italic>, <jats:italic>gpx4<\/jats:italic>, and <jats:italic>xct<\/jats:italic>) and iron storage related genes (<jats:italic>tf<\/jats:italic>, <jats:italic>fth<\/jats:italic>, and <jats:italic>fpn<\/jats:italic>) in zebrafish embryos. Through in vitro verification, it was found that IBC also caused oxidative stress and increased Fe<jats:sup>2+<\/jats:sup> content in HepG2 cells. IBC caused depolarization of mitochondrial membrane potential (MMP) and reduction of mitochondrial ATP, as well as altered expression of ACSl4, SLC7A11, GPX4, and FTH1 proteins. Treatment of HepG2 cells with ferrostatin\u20101 could reverse the effect of IBC. Targeting the System Xc<jats:sup>\u2212<\/jats:sup>\u2010GSH\u2010GPX4 pathway of ferroptosis and preventing oxidative stress damage might offer a theoretical foundation for practical therapy and prevention of IBC\u2010induced hepatotoxicity.<\/jats:p>","DOI":"10.1002\/jat.4607","type":"journal-article","created":{"date-parts":[[2024,4,6]],"date-time":"2024-04-06T03:14:55Z","timestamp":1712373295000},"page":"1139-1152","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Isobavachalcone induces hepatotoxicity in zebrafish embryos and HepG2 cells via the System Xc<sup>\u2212<\/sup>\u2010GSH\u2010GPX4 signaling pathway in ferroptosis response"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9519-2862","authenticated-orcid":false,"given":"Xuan","family":"Ni","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine Xinjiang Agricultural University  Urumqi 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