Sorafenib Restores Pentose Phosphate Pathway‐Related Redox Homeostasis via the c‐Raf/HSP90/G6PD Axis in Hepatic Ischemia‐Reperfusion Injury

ABSTRACT Hepatic ischemia reperfusion injury (IRI) is a frequent complication of liver surgery and is strongly associated with poorer recipient survival. Sorafenib, a multi‐kinase inhibitor, has been implicated in hepatic metabolic and redox regulation, yet its role in hepatic IRI remains unclear. Our study finds that middle‐dose sorafenib protects the liver from IRI by reducing hepatic necrosis, inflammation, and apoptosis. Mechanistically, transcriptomic and metabolomics analyses confirm that middle‐dose sorafenib enhances pentose phosphate pathway‐mediated antioxidant activity through the c‐rapidly accelerated fibrosarcoma (c‐Raf)/heat shock protein 90 (HSP90)/glucose‐6‐phosphate dehydrogenase (G6PD) axis. Co‐immunoprecipitation, Western blot, and confocal immunofluorescence analyses demonstrate the direct binding interaction between HA‐c‐Raf and Myc‐HSP90, as well as between Flag‐G6PD and Myc‐HSP90. 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‐dose sorafenib, particularly when delivered via the novel oral nanoplatform, as an effective strategy to mitigate hepatic IRI.