Obesity-Induced PLPE-PTK6-FASN Feedback Loop Drives Enzalutamide Resistance by Exacerbating Lipid Metabolic Dysregulation in Castration-Resistant Prostate Cancer

Obesity represents an independent risk factor for various malignancies, including prostate cancer. However, how specific lipid metabolites influence enzalutamide sensitivity in castration-resistant prostate cancer (CRPC) remains elusive. Here, we find that obesity is associated with poorer clinical outcomes during enzalutamide treatment. Lipidomic profiling reveals that 1-palmitoyl-2-linoleoyl phosphatidylethanolamine (PLPE) is markedly enriched in tumors from these individuals. Mechanistically, elevated PLPE directly binds to the SH2 domain of protein tyrosine kinase 6 (PTK6), driving its membrane translocation and functional activation. Furthermore, PLPE facilitates PTK6-fatty acid synthase (FASN) interaction, enabling PTK6 to mediate FASN phosphorylation at T976 via dual mechanisms: steric occupancy and kinase cascade amplification. This hyperactivation of FASN exacerbates lipid metabolic dysregulation, ultimately conferring enzalutamide resistance. Importantly, FASN-derived palmitic acid serves as a substrate for further PLPE synthesis, thereby reinforcing PTK6 membrane retention in a positive feedback loop. Collectively, this study identifies a PLPE-PTK6-FASN feedback loop that drives lipid metabolic reprogramming and enzalutamide resistance in CRPC with obesity, highlighting the therapeutic potential of cotargeting lipid metabolism and kinase signaling.