Mitochondrial convergence of ferroptosis and cuproptosis in castration-resistant prostate cancer: From metabolic vulnerabilities to therapeutic targeting.

Castration-resistant prostate cancer (CRPC) represents the lethal stage of prostate cancer progression and is characterized by persistent therapeutic adaptation, androgen receptor (AR) signaling rewiring, and profound metabolic reprogramming. In recent years, ferroptosis and cuproptosis, two forms of metal-dependent regulated cell death, have emerged as potentially important therapeutic vulnerabilities in CRPC. Ferroptosis is primarily driven by iron-dependent lipid peroxidation, whereas cuproptosis is characterized by copper-induced proteotoxic stress of mitochondrial lipoylated proteins and consequent metabolic collapse. Although these two cell death modalities are mechanistically distinct, accumulating evidence suggests that mitochondria may serve as a critical point of convergence linking them. Mitochondrial metabolic dependency, iron-sulfur cluster homeostasis, lipoylation pathways, membrane organization, and mitochondrial quality control networks collectively shape the susceptibility of CRPC cells to ferroptosis and cuproptosis. In this review, we summarize the mitochondrial basis of ferroptosis and cuproptosis in CRPC and propose that their relationship is better understood as a shared mitochondrial vulnerability architecture rather than as an identical terminal execution pathway. Furthermore, we discuss how mitochondrial metal-death vulnerability may represent a therapeutically exploitable architecture in CRPC, providing a rationale for combination strategies that target ferroptosis, cuproptosis, and mitochondrial metabolic dependency.