Flavonoid GL-V9 as a novel and potent acetyl-coa carboxylase 1 inhibitor confers cisplatin hypersensitivity in ovarian cancer

BACKGROUND: Cisplatin has been a cornerstone of Ovarian cancer (OC) treatment since its clinical introduction in the 1970s, with platinum-based regimens forming the core of first-line therapy. However, approximately 70% of patients eventually experience disease recurrence and develop resistance to platinum. To date, few clinically viable alternatives to cisplatin have emerged for the effective management of OC. PURPOSE: Therefore, this study aims to identify a novel agent capable of enhancing cisplatin sensitivity and overcoming chemoresistance in ovarian cancer. STUDY DESIGN: This study evaluates the anti-tumor effects of GL-V9 in ovarian cancer, elucidates its underlying mechanisms, and evaluates its potential for clinical translation. METHODS: The mechanisms underlying the effects of GL-V9 were investigated using streptavidin pull-down assays, functional analyses (cell viability, clonogenic survival, and apoptosis), and Western blotting. The antitumor efficacy of GL-V9 alone and in combination with cisplatin was further evaluated in an A2780 ovarian cancer xenograft model. RESULTS: We found that GL-V9, a flavonoid derived from Scutellaria, exerted potent antitumor effects in OC by inducing apoptosis and inhibiting proliferation. Furthermore, GL-V9 enhanced cisplatin sensitivity and reversed cisplatin resistance. Mechanistically, GL-V9 directly bound to and inhibited acetyl-CoA carboxylase 1 (ACC1), leading to elevated intracellular reactive oxygen species (ROS) levels. Both in vitro and in vivo experiments confirmed that GL-V9, alone or in combination with cisplatin, significantly suppressed tumor growth without observable toxicity. CONCLUSION: GL-V9 overcomes cisplatin resistance in ovarian cancer by targeting ACC1 and elevating ROS levels, highlighting its potential as a clinically translatable therapeutic strategy.