Targeting Melatonin to Mitochondria Mitigates Castration-Resistant Prostate Cancer by Inducing Pyroptosis

Prostate cancer frequently progresses to castration-resistant prostate cancer (CRPC) following androgen deprivation therapy, presenting a significant clinical challenge. Targeting tumor metabolism, particularly mitochondrial pathways, offers a promising strategy for overcoming CRPC. The modification of melatonin (Mel) to a triphenylphosphonium (TPP) cation-targeted mitochondria–melatonin (Mito–Mel) significantly increases its potency by over 1000-fold. Mito–Mel selectively targets mitochondria, enhancing reactive oxygen species (ROS) generation and causing mitochondrial membrane potential disruption. This leads to the inhibition of mitochondrial respiration including the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), which, in turn, suppresses CRPC survival metabolic adaptations, such as glycolysis. In vitro and in vivo experiments reveal for the first time that natural small molecule compound with mitochondrial targeting via TPP exhibits excellent anticancer efficacy by inducing tumor cellular pyroptosis and facilitating the immune response, underlining the encouraging promise of this strategy for the effective treatment of CRPC.