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Sorafenib, a multi\u2010kinase inhibitor, has been implicated in hepatic metabolic and redox regulation, yet its role in hepatic IRI remains unclear. Our study finds that middle\u2010dose sorafenib protects the liver from IRI by reducing hepatic necrosis, inflammation, and apoptosis. Mechanistically, transcriptomic and metabolomics analyses confirm that middle\u2010dose sorafenib enhances pentose phosphate pathway\u2010mediated antioxidant activity through the c\u2010rapidly accelerated fibrosarcoma (c\u2010Raf)\/heat shock protein 90 (HSP90)\/glucose\u20106\u2010phosphate dehydrogenase (G6PD) axis. Co\u2010immunoprecipitation, Western blot, and confocal immunofluorescence analyses demonstrate the direct binding interaction between HA\u2010c\u2010Raf and Myc\u2010HSP90, as well as between Flag\u2010G6PD and Myc\u2010HSP90. Meanwhile, the overexpression of HSP90 disrupts the benefits of sorafenib on hepatic IRI, and inhibition of G6PD also rescues its protective effect. Notably, in human liver transplant recipients, elevated HSP90 levels correlated with poor graft function and survival, supporting its clinical relevance. Furthermore, a novel oral nanoparticle delivery system, targeting the liver tissue, enhances the therapeutic efficacy of sorafenib, restoring liver enzyme levels by up to 76%. Collectively, these findings identify middle\u2010dose sorafenib, particularly when delivered via the novel oral nanoplatform, as an effective strategy to mitigate hepatic IRI.<\/jats:p>","DOI":"10.1002\/mco2.70819","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T06:35:33Z","timestamp":1782110133000},"source":"Crossref","is-referenced-by-count":0,"title":["Sorafenib Restores Pentose Phosphate Pathway\u2010Related Redox Homeostasis via the c\u2010Raf\/HSP90\/G6PD Axis in Hepatic Ischemia\u2010Reperfusion Injury"],"prefix":"10.1002","volume":"7","author":[{"given":"Fengqiang","family":"Gao","sequence":"first","affiliation":[{"name":"Hepatobiliary Center the First A\ufb03liated Hospital with Nanjing Medical University Nanjing China"},{"name":"Institute of Translational Medicine Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libin","family":"Dong","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yawen","family":"Tan","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The First Affiliated Hospital of Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengjun","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary &amp; 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