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Ginsenoside Rg5 (Rg5) can exert protective effects on the liver and activate the Nrf2 pathway. This study aims to investigate the mechanism of Rg5 alleviating acute liver injury (ALI), and the related mechanisms will be discussed. In\u00a0vitro experiments, an ALI model was established using HepG2 cells. The DCFHDA, the JC\u20101, and the ferrous ion fluorescent probe detected the reactive oxygen species (ROS) level, the mitochondrial membrane potential change, and the iron ions level. The oxidative stress indexes were detected by biochemical analysis. Western blot was used to detect the m6A demethylation, Nrf2, and ferroptosis signaling pathways. For in\u00a0vivo experiments, C57BL\/6J mice were administered ethanol by gavage to establish the ALI model. In\u00a0vitro, we observed that m\n                    <jats:sup>6<\/jats:sup>\n                    A methylation and FTO downregulation were involved in the ferroptosis process. Rg5 treatment alleviated ferroptosis after ethanol exposure, which was reflected by the decrease of intracellular iron content and ferroptosis\u2010related proteins. The FTO knockdown exhibited ferroptosis\u2010related proteins and YTHDF2 increase. The regulatory effect of FTO on ferroptosis was inhibited when Nrf2 was inhibited or knocked down. In\u00a0vivo, HE staining revealed liver injury in the model group, with elevated liver\u2010to\u2010body weight ratios and serum ALT and AST levels. The Rg5 treatment has improved these phenomena. FTO, Nrf2, and anti\u2010ferroptosis proteins were downregulated in the ethanol group, while the ferroptosis marker ACSL4 was upregulated. This study demonstrates that Rg5 alleviates ethanol\u2010induced ALI by inhibiting ferroptosis via the FTO\/YTHDF2\/Nrf2 axis. Our work not only establishes a link between FTO\u2010mediated m\n                    <jats:sup>6<\/jats:sup>\n                    A demethylation and ferroptosis but also provides new mechanistic insights into the hepatoprotective action of ginsenosides.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70373","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T06:54:17Z","timestamp":1778482457000},"page":"4485-4500","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Ginsenoside Rg5 Ameliorates Ferroptosis in Ethanol\u2010Induced Acute Liver Injury by Activating\n                    <scp>FTO<\/scp>\n                    \u2010\n                    <scp>YTHDF2<\/scp>\n                    \u2010Nrf2 Signal"],"prefix":"10.1002","volume":"40","author":[{"given":"Guan\u2010Yue","family":"Shan","sequence":"first","affiliation":[{"name":"Department of Bioengineering Jilin University School of Pharmaceutical Sciences  Changchun China"},{"name":"Laboratory for Tumor Immunology The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory for Tumor Immunology The First Hospital of Jilin University  Changchun China"},{"name":"China\u2010Singapore Belt and Road Joint Laboratory on Liver Disease Research The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wan","sequence":"additional","affiliation":[{"name":"Laboratory for Tumor Immunology The First Hospital of Jilin University  Changchun China"},{"name":"China\u2010Singapore Belt and Road Joint Laboratory on Liver Disease Research The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Jilin University School of Pharmaceutical Sciences  Changchun China"},{"name":"Laboratory for Tumor Immunology The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi\u2010Cheng","family":"Gao","sequence":"additional","affiliation":[{"name":"Laboratory for Tumor Immunology The First Hospital of Jilin University  Changchun China"},{"name":"China\u2010Singapore Belt and Road Joint Laboratory on Liver Disease Research The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi\u2010Jun","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Jilin University School of Pharmaceutical Sciences  Changchun China"},{"name":"Laboratory for Tumor Immunology The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Qun","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Jilin University School of Pharmaceutical Sciences  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun\u2010Peng","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery China\u2010Japan Union Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2515-3076","authenticated-orcid":false,"given":"Hai\u2010jun","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory for Tumor Immunology The First Hospital of Jilin University  Changchun China"},{"name":"China\u2010Singapore Belt and Road Joint Laboratory on Liver Disease Research The First Hospital of Jilin University  Changchun 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