Mitochondria-mediated ferroptosis a novel therapeutic target in castration-resistant prostate cancer

Castration-resistant prostate cancer (CRPC) represents the terminal stage of prostate cancer progression, with its lethality stemming from the loss of sensitivity to most current systemic therapies. Although next-generation androgen receptor-targeted drugs have extended patient survival to some extent, durable disease control remains limited by the profound plasticity of tumor cells and the metabolic adaptive reprogramming triggered by therapeutic pressure. Ferroptosis, a novel form of regulated cell death driven by iron-dependent lipid peroxidation, has seen exponential growth in research since its discovery in 2012. Chemoresistant cancer cells, particularly those that acquire a mesenchymal phenotype with high metastatic potential, are particularly sensitive to ferroptosis, making it a potential vulnerability in combating CRPC. However, the specific determinants of ferroptosis sensitivity in CRPC remain incompletely understood. Here, we review the known execution and regulatory mechanisms of ferroptosis and discuss its critical biological significance in CRPC. Mitochondria, as the central hub for iron metabolism, redox homeostasis, and cellular bioenergetics, play a pivotal role in regulating ferroptosis. Increasing evidence suggests that under sustained therapeutic pressure, CRPC cells undergo reorganization of core mitochondrial molecular interactions, metabolic pathway reprogramming, and dynamic remodeling of mitochondrial structure and function. These adaptive changes collectively raise the threshold for ferroptosis, enabling tumor cells to survive in conditions that would otherwise induce lethal lipid peroxidation. This review integrates current insights into mitochondria-mediated ferroptosis in CRPC, systematically exploring how this axis contributes to the development of therapeutic resistance. Finally, we focus on the potential of targeting mitochondrial ferroptosis to enhance CRPC immunotherapy, offering theoretical guidance and direction for the development of novel therapeutic strategies aimed at overcoming treatment resistance and improving patient prognosis.