Reprogrammed Lipid Metabolism-Associated Therapeutic Vulnerabilities in Prostate Cancer.

Prostate cancer (PCa), the second leading cause of cancer-related mortality among men in the United States, is marked by profound metabolic reprogramming, particularly in lipid metabolism. This review highlights the pivotal role of altered lipid metabolic pathways, including de novo fatty acid synthesis, fatty acid uptake and transport, β-oxidation, and cholesterol metabolism, in the development, progression, and therapeutic resistance of PCa. Key enzymes and transcription factors, such as FASN, ACLY, SREBPs, and FABPs, which are mainly regulated by androgen receptor signaling, orchestrate a lipogenic phenotype that supports prostate tumor growth and survival. Crosstalk between lipid metabolism and the tumor microenvironment further promotes immune evasion and metastasis. The review also explores therapeutic opportunities in targeting lipid metabolic pathways, highlighting the preclinical and clinical advances in inhibiting FASN, SREBP1, SREBP2, HMGCR, and FABPs, as well as combinatorial strategies with conventional therapies. Understanding the impact of lipid metabolism on PCa pathogenesis provides a promising avenue for developing novel targeted and combinatorial interventions to improve clinical outcomes in PCa.