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.

The metastasis-associated protein 1/protein kinase B (MTA1/AKT) signaling pathway has been shown to cooperate in promoting prostate tumor growth. Targeted interception strategies by plant-based polyphenols, specifically stilbenes, have shown great promise against MTA1-mediated prostate cancer progression. In this study, we employed a prostate-specific transgenic mouse model with MTA1 overexpression on the background of phosphatase and tensin homolog (Pten) null (R26^MTA1; Pten^f/f) and PC3M prostate cancer cells which recapitulate altered molecular pathways in advanced prostate cancer. Mechanistically, the MTA1 knockdown or pharmacological inhibition of MTA1 by gnetin C (dimer resveratrol) in cultured PC3M cells resulted in the marked inactivation of mammalian target of rapamycin (mTOR) signaling. In vivo, mice tolerated a daily intraperitoneal treatment of gnetin C (7 mg/kg bw) for 12 weeks without any sign of toxicity. Treatment with gnetin C markedly reduced cell proliferation and angiogenesis and promoted apoptosis in mice with advanced prostate cancer. Further, in addition to decreasing MTA1 levels in prostate epithelial cells, gnetin C significantly reduced mTOR signaling activity in prostate tissues, including the activity of mTOR-target proteins: p70 ribosomal protein S6 kinase (S6K) and eukaryotic translational initiation factor 4E (elF4E)-binding protein 1 (4EBP1). Collectively, these findings established gnetin C as a new natural compound with anticancer properties against MTA1/AKT/mTOR-activated prostate cancer, with potential as monotherapy and as a possible adjunct to clinically approved mTOR pathway inhibitors in the future.