Abstract

Background:Sirtuin 3 (SIRT3) is a key mitochondrial regulator that functions as an oncogene in breast cancer, where its overexpression drives chemoresistance. Targeting SIRT3 offers a strategy to overcome resistance mechanisms and improve chemotherapy efficacy.Methods:We utilized molecular docking-based virtual screening to identify SIRT3 inhibitors from a natural product library. Candidates were validated via molecular dynamics simulations and binding assays. Efficacy was tested in breast cancer cells and an orthotopic mouse model by assessing cell viability, apoptosis, mitochondrial function, and tumor growth during cisplatin treatment.Results:Jionoside B1 was identified as a potent SIRT3 inhibitor that suppresses enzymatic activity, leading to increased SOD2 acetylation. In breast cancer cells, Jionoside B1 significantly enhanced cisplatin sensitivity by promoting ROS accumulation, disrupting mitochondrial potential, and triggering apoptosis. In vivo, the combination of Jionoside B1 and cisplatin inhibited tumor growth more effectively than cisplatin alone.Conclusions:Jionoside B1 sensitizes breast cancer cells to cisplatin by inhibiting SIRT3-mediated oxidative stress defense. These findings highlight Jionoside B1 as a promising therapeutic candidate for combination chemotherapy to enhance cisplatin responsiveness in breast cancer.