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Targeting tumor metabolism, particularly mitochondrial pathways, offers a promising strategy for overcoming CRPC. The modification of melatonin (Mel) to a triphenylphosphonium (TPP) cation\u2010targeted mitochondria\u2013melatonin (Mito\u2013Mel) significantly increases its potency by over 1000\u2010fold. Mito\u2013Mel 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.<\/jats:p>","DOI":"10.1002\/smll.202408996","type":"journal-article","created":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T06:11:42Z","timestamp":1745647902000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Targeting Melatonin to Mitochondria Mitigates Castration\u2010Resistant Prostate Cancer by Inducing Pyroptosis"],"prefix":"10.1002","volume":"21","author":[{"given":"Xiaohui","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory The Fifth Affiliated Hospital Sun Yat\u2010sen University  Zhuhai Guangdong 519000 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