Abstract

Hepatocellular carcinoma (HCC), a globally prevalent malignant tumor, faces therapeutic challenges due to chemotherapy resistance. Although squalene has demonstrated anti-tumor and resistance reversal potential, its mechanism of action in HCC drug resistance remains to be fully elucidated. Doxorubicin (DOX)-resistant HCC cell models were established. The impact of SIRT6 on DOX resistance was assessed using CCK-8, colony formation, flow cytometry, and Western blot of apoptosis-related proteins. The binding between squalene and SIRT6 was verified by molecular docking and cellular thermal shift assay. The effect of SIRT6 on ERK1 deacetylation was predicted bioinformatically and confirmed by co-immunoprecipitation and immunofluorescence. Finally, a nude mouse xenograft model was established to validate that squalene overcomes DOX resistance in HCC by targeting SIRT6 in vivo. SIRT6 knockdown suppressed the viability and proliferation of DOX-resistant cells and enhanced apoptosis. SIRT6 functions by regulating ERK1 deacetylation. SIRT6 inhibition increased ERK1 acetylation and reduced the expression of phosphorylated ERK1/2 (p-ERK1/2). Squalene effectively reversed DOX resistance by targeting SIRT6 to inhibit ERK1 deacetylation in HCC cells. Squalene suppresses DOX resistance by targeting SIRT6 to inhibit ERK1 deacetylation in HCC. The study provides novel molecular insights and identifies a druggable target for HCC therapy.