Suppression of de novo lipogenesis and dietary PUFA supplementation inhibit prostate cancer progression

Prostate cancer progression is characterized by dysregulated lipid metabolism, with activation of fatty acid synthase (FASN), the rate-limiting step in de novo lipogenesis (DNL), resulting in significant accumulation of saturated lipids. Here, we show that pharmacologic FASN inhibition creates a metabolic state that increases reliance on exogenous polyunsaturated fatty acids (PUFAs). Inhibition of FASN profoundly alters membrane phospholipid composition, driving compensatory incorporation of PUFAs into membrane phospholipids, thus increasing susceptibility to lipid peroxidation and oxidative damage. Combined FASN inhibition and PUFA exposure induce mitochondrial hyperpolarization and enhance lipid peroxidation in both hormone-sensitive and castration-resistant prostate cancer models, resulting in increased reactive oxygen species production, ferroptosis, as well as apoptosis. Marked inhibition of growth in castration-resistant human and murine prostate cancer organoids is achieved ex vivo. In genetically engineered, DNL-reliant Hi-Myc mice, a diet enriched in PUFAs significantly inhibited invasive carcinoma compared to a saturated fat-enriched diet. Thus, environmental PUFAs modulate and enhance the therapeutic efficacy of FASN-targeted strategies. These findings set the stage for pharmacologic and dietary intervention in prostate cancer patients.