Adipose triglyceride lipase driven lipolysis as a targetable metabolic vulnerability in prostate cancer with intrinsic metabolic inflexibility

BACKGROUND: Despite the widespread clinical use of prostate-specific membrane antigen (PSMA)-targeted imaging and therapy in prostate cancer, the biological functions underlying PSMA-associated tumour aggressiveness remain incompletely understood. METHODS: PSMA-PET-guided sampling of paired PSMA-high and PSMA-low tumour regions was used for integrated proteomic and epigenomic analyses. PSMA-ATGL correlation was validated by immunohistochemistry in 90 treatment-naïve patients. Metabolic profiling was performed using Seahorse Mito Fuel Flex Test assays under unperturbed conditions and pharmacological or genetic perturbation of ATGL and PSMA. Therapeutic vulnerability was assessed using NG-497 and siRNA-mediated knockdown. RESULTS: PSMA-high tumours exhibited lipolytic reprogramming characterised by ATGL upregulation, confirmed by a robust PSMA-ATGL correlation in the validation cohort (P < 0.0001). Despite shared fatty acid dependency, LNCaP cells exhibited intrinsic metabolic inflexibility while 22RV1 cells displayed high adaptability. Both pharmacological and genetic ATGL inhibition most potently impaired LNCaP proliferation. Enzalutamide upregulated ATGL in both cell lines, revealing reciprocal regulation between AR signaling and the PSMA/ATGL axis. CONCLUSIONS: ATGL-mediated lipolysis represents a promising therapeutic target in prostate cancer, with heightened sensitivity in tumours lacking metabolic flexibility to utilize alternative pathways.