SIRT3 suppresses renal cancer progression by regulating IDH2 acetylation.

Metabolic reprogramming is a hallmark characteristic of renal cell carcinoma (RCC). SIRT3, a key mitochondrial deacetylase, plays a crucial role in metabolic reprogramming. However, its contribution to RCC development remains unclear. Bioinformatics analysis and immunohistochemistry results showed reduced SIRT3 expression in RCC and its correlation with RCC malignancy. SIRT3 knockdown enhanced cell proliferation and colony formation abilities, suggesting that SIRT3 suppresses RCC progression. Mechanistically, knockdown of SIRT3, increases the level of acetylation of isocitrate dehydrogenase 2 (IDH2) at lysine K413 (IDH2(K413ac)), which impairs its enzymatic activity, mitochondrial function and redox balance. This effect was reversed by the IDH2 acetylation-mimic mutant K413Q but not by the deacetylation-mimic mutant K413R. Honokiol (HKL), a SIRT3 activator, inhibited RCC cell proliferation and colony formation by increasing SIRT3 levels. Our findings identify a novel mechanism by which SIRT3 suppressed RCC progression. SIRT3 acts as a promising therapeutic target for RCC, with HKL as a potential novel therapeutic agent. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-37783-6.