Discovery of Natural Compound α-Hederin via Large-Scale Screening as a Targeted JAK/STAT3 Inhibitor for Ovarian Cancer Therapy.

Chemoresistance and metastasis are key obstacles to successful ovarian cancer (OC) treatment. Here, α-Hederin, a pentacyclic triterpenoid saponin, is identified as a potent and selective dual inhibitor of JAK1/JAK2 with promising therapeutic potential in OC. Integrating transcriptomic analysis, virtual screening, molecular docking, and biochemical validation, it is shown that α-Hederin directly binds the JH1 kinase domains of JAK1 and JAK2, suppressing their activity and downstream STAT3 phosphorylation. α-Hederin inhibits OC cell proliferation, epithelial-mesenchymal transition (EMT), and metastasis in vitro, and suppresses tumor growth and dissemination in multiple mouse models, with minimal systemic toxicity. Mechanistically, α-Hederin blocks STAT3 nuclear translocation and downregulates oncogenic STAT3 targets including MYC, CCND1, and TWIST1. Rescue experiments using the STAT3 agonist Colivelin partially reversed these effects, confirming the JAK/STAT3 axis as a key target. Moreover, α-Hederin synergizes with cisplatin to enhance antitumor efficacy and overcomes platinum resistance in OC cells. Collectively, our findings highlight α-Hederin as a safe and effective natural JAK1/2 inhibitor that suppresses OC progression by targeting the JAK/STAT3 pathway, offering a compelling candidate for future clinical translation.