HSP90AA1 inhibits the Jun/Fos pathway to rescue hepatocytes from cuproptosis during ischemia-reperfusion injury.

Hepatic ischemia-reperfusion injury (HIRI), a frequent complication in procedures like hepatic lobectomy and organ transplantation, remains a significant clinical challenge despite advances in protective strategies. Cuproptosis, a copper-dependent form of cell death, has recently been linked to various inflammatory diseases, including HIRI. In this study, bioinformatic analyses were employed to identify differentially expressed core genes, and animal and cellular models of HIRI were established using C57BL/6 mice and AML12 cells to investigate the roles of HSP90AA1 and c-Jun/c-Fos-mediated cuproptosis in HIRI. Techniques including RT-qPCR, Western blotting, immunohistochemistry, immunofluorescence, and electron microscopy were used to assess cuproptosis, inflammation, and mitochondrial damage. Bioinformatic results indicated that HSP90AA1 and the Jun/Fos pathway are likely key targets in HIRI. Notably, increased cuproptosis and elevated HSP90AA1 expression in hepatocytes were observed both in vivo and in vitro following HIRI. Furthermore, HSP90AA1 overexpression significantly attenuated I/R-induced liver injury and cuproptosis by suppressing the Jun/Fos pathway. These findings reveal, for the first time, that HSP90AA1 can mitigate cuproptosis induced by HIRI via regulation of the Jun/Fos pathway, suggesting a potential novel therapeutic approach for HIRI.