Rewired lipid metabolism in castration-resistant prostate cancer: molecular interplay between glucose metabolism and sterol synthesis.

Castration-resistant prostate cancer (CRPC) is a stage of prostate cancer that is progressed and resistant to treatment. Intra-tumoral androgen production, as well as substantial metabolic reprogramming, present significant treatment hurdles. De novo lipogenesis (DNL) is emerging as a key metabolic signature of CRPC, supporting tumour development, intra-tumoral androgen synthesis, membrane biosynthesis, energy production, and oncogenic signaling. Importantly, lipogenesis in CRPC is supported by upstream metabolic feeders such as increased glycolysis, rewired tricarboxylic acid (TCA) cycle activity, and amino acid metabolism, which work altogether to provide a steady supply of lipid and sterol precursors. This review summarizes the metabolic crosstalk linking Glucose to sterols in CRPC progression and highlights how these pathways cooperate to maintain androgen biosynthesis and therapeutic resistance. In addition, we highlight the emerging role of phytochemicals as multi-target metabolic modulators capable of suppressing overactivated lipogenesis, thereby reducing treatment-associated toxicity. Overall, this review highlights lipogenesis-centered metabolic targeting as a promising strategy to overcome metabolic plasticity, minimize conventional drug dosage and achieve therapy durability in CRPC, especially through logical combination techniques using phytochemical adjuvants.