SIRT3 promotes oxaliplatin sensitivity in hepatocellular carcinoma by promoting ferroptosis through endoplasmic reticulum stress response.

Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide. The specific role of Sirtuin3 (SIRT3), a member of the Sirtuin family, in HCC, particularly regarding drug sensitivity, has not been fully elucidated. This study aimed to elucidate the mechanism by which SIRT3 modulates drug sensitivity in HCC. Expression prediction of target genes, survival analysis, and candidate protein screening were conducted using bioinformatics databases. After transfection of different plasmids in HCC cells, the expression of target genes was detected using RT-qPCR and Western blot. CCK-8 assay was used to assess the effect of SIRT3 overexpression on the proliferation ability of HCC cells. Additionally, changes in ferroptosis levels in HCC cells were reflected by detecting ferroptosis-related indicators (including ROS, MDA, GSH, and Fe2+ levels). SIRT3 was downregulated in HCC and its overexpression promoted sensitivity of HCC cells to oxaliplatin. Mechanistically, SIRT3 induced deacetylation modification and ubiquitination modification of GRP78, leading to a decrease in its stability and subsequent degradation of GRP78 protein. This process limited the correction of misfolded proteins during endoplasmic reticulum stress (ERS). The inhibition of the downstream transcription factor of ER stress ATF4 activation leads to the suppression of the anti-ferroptosis gene NRF2 transcription, thereby promoting ferroptosis in HCC cells and enhancing their sensitivity to oxaliplatin. In summary, SIRT3 enhances the sensitivity of HCC cells to oxaliplatin by promoting ferroptosis through the inhibition of GRP78-mediated ERS and regulation of the ATF4/NRF2 axis.