Targeting mitochondrial metabolism in renal cell carcinoma with melatonin: Preclinical evidence and clinical perspectives.

RCC is characterized by mitochondrial dysfunction, oxidative stress, and resistance to traditional therapies such as tyrosine kinase inhibitors (TKIs). Melatonin, a pleiotropic neurohormone, has emerged as a viable treatment for renal cell carcinoma (RCC) by targeting metabolic dysregulation and carcinogenic signaling pathways. This review summarizes current experimental and clinical data that melatonin can restore mitochondrial oxidative phosphorylation, reverse the Warburg metabolic phenotype, and modify redox homeostasis. Melatonin suppresses cancer-driving pathways such as Akt-mTOR, NF-κB, HIF-1/VEGFA, and MAPKs, leading to reduced tumor growth, angiogenesis, invasion, and increased apoptosis and autophagy. Melatonin receptor subtypes MT1, MT2, and MT3 have various signaling effects that contribute to its anti-tumor and immunomodulatory properties. Importantly, melatonin works with TKIs like sunitinib and pazopanib to improve mitochondrial homeostasis and increase therapeutic effectiveness. Its regulation of inflammatory cytokines and death receptor pathways enhances immune-mediated tumor suppression. Overall, melatonin provides a multi-targeted, low-toxicity strategy for overcoming metabolic and therapeutic resistance in RCC, emphasizing its translational promise as an adjuvant. Further clinical trials should concentrate on dose optimization, biomarker-guided patient selection, and combination regimens that include immune checkpoint blockade.