Bavachinin exerts anti-tumor effects by activating TLR4/STING axis-dependent PANoptosis and synergistically enhances chemosensitivity in endometrial cancer

The incidence and mortality rates of endometrial cancer (EC), a malignancy originating from endometrium, have been increasing globally. Currently, there are no effective therapeutic options for patients with recurrent, chemoresistant, and metastatic forms of this disease. Through compound library screening, we identified that bavachinin (BVC) has a killing effect on EC cells. BVC is a bioactive small molecule with potential pharmacological effects derived from the traditional Chinese herb Proralea corylifolia L, but the specific mechanisms are unclear. We first discovered that BVC induces ZBP1 (Z-DNA binding protein 1)-mediated PANoptosis in EC cells, characterized by activating of pyroptosis, apoptosis, and necroptosis. BVC promoted reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP, ΔΨm) collapse, and ATM-CHK2 mediated DNA damage, which activated cGAS-STING pathway in EC cells. Mechanistically, network pharmacology, molecular docking, cellular thermal shift assays (CESTA), and drug affinity responsive target stability (DARTS) experiments revealed that BVC induced PANoptosis in EC cells by directly interacting with toll-like receptor 4 (TLR4), thereby triggering mitochondrial ROS generation, activating the cGAS-STING pathway. Notably, TLR4 knockdown inhibited STING-TBK1-IRF3 pathway and ZBP1-mediated PANoptosis. In addition, low-dose BVC combined with cisplatin increased phosphorylated H2AX expression, suggesting that BVC enhances the sensitivity of EC cells to cisplatin. In vivo studies demonstrated that BVC induced PANoptosis in EC, and BVC in combination with cisplatin had effective anti-tumor effect without injuring vital organs. These novel findings provide compelling evidence to support the clinical application of BVC and PANoptosis-based therapy for treating EC.