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

Abstract

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.