Ziyin Jianghuo decoction induces ferroptosis through the DTX3L/p53 pathway to inhibit prostate cancer

Prostate cancer (PCa) is a leading cause of cancer-related mortality. While traditional Chinese medicine holds promise in oncology, the therapeutic efficacy and mechanisms of Ziyin Jianghuo Decoction (ZYJHD) in PCa remain unclear. Through in vitro and in vivo experiments, we demonstrated that ZYJHD significantly inhibits PCa progression by promoting apoptosis and inducing ferroptosis. Mechanistically, ZYJHD downregulates deltex E3 ubiquitin ligase 3L (DTX3L) to prevent DTX3L-mediated p53 ubiquitination and degradation. This stabilizes p53 and enhances ferroptotic signaling. DTX3L overexpression reversed the anti-tumor effects of ZYJHD, whereas the ferroptosis inducer erastin re-sensitized the cells to ZYJHD-induced ferroptosis. Furthermore, pharmacological inhibition of p53 attenuated ZYJHD-mediated tumor suppression and ferroptosis. Collectively, ZYJHD exerts its anti-PCa effects by targeting the DTX3L/p53/ferroptosis axis, highlighting its potential as a therapeutic agent for advanced PCa, including metastatic castration-sensitive and castration-resistant subtypes.