Inhibition of SIRT3 by a specific inhibitor induces cellular senescence and growth arrest of ovarian granulosa cell tumor via p53 and NF-κB axis.

Objectives: Ovarian granulosa cell tumors (GCTs) are rare ovarian malignancies with limited therapeutic options, particularly in advanced stages. SIRT3, an NAD + -dependent deacetylase, is upregulated in GCTs and implicated in tumorigenesis, yet its functional role and underlying mechanisms remain poorly understood. This study aims to investigate the therapeutic efficacy of a novel SIRT3-specific inhibitor, 77-39, in GCTs by targeting SIRT3 and to elucidate the molecular mechanisms underlying its effects. Methods: This study investigated the effects of a SIRT3-specific inhibitor, 77-39, on GCT cell growth and explored its underlying mechanisms. Using human GCT cell lines KGN and COV434, we assessed the impact of 77-39 on cell viability and proliferation. RNA sequencing and gene set enrichment analyses were performed to elucidate the pathways affected by 77-39. Western blot assays were used to confirm the activation of specific signaling pathways. Additionally, SIRT3 was silenced or overexpressed to observe the corresponding effects on GCT cells. Results: We demonstrated that 77-39 significantly suppressed cell viability and proliferation while inducing cellular senescence in human GCT cell lines KGN and COV434. RNA sequencing and gene set enrichment analyses revealed that 77-39 led to the activation of the p53 and NF-κB signaling pathways, which were confirmed by Western blot assay. Silencing SIRT3 recapitulated the effects of 77-39, while SIRT3 overexpression reversed these effects. Inhibition of p53 or NF-κB rescued GCT cells from 77-39-induced growth arrest and senescence. Conclusion: These findings suggest that 77-39 may serve as a novel therapeutic agent for GCTs by targeting SIRT3 and modulating the p53 and NF-κB pathways.