ATGL-driven lipolysis defines a targetable metabolic vulnerability in PSMA-high prostate cancer

ABSTRACT: Prostate-specific membrane antigen (PSMA) is a validated biomarker and therapeutic target in prostate cancer, yet its biological functions remain incompletely understood. Using PSMA-Positron Emission Tomography imaging-guided sampling, we performed integrated proteomic and epigenetic analyses of PSMA-high versus PSMA-low areas within primary prostate tumors, revealing an association between high PSMA expression and lipolytic metabolic reprogramming. This reprogramming was characterized by increased adipose triglyceride lipase (ATGL) protein expression, accompanied by promoter hypomethylation of its encoding gene PNPLA2. We validated the PSMA-ATGL correlation in an independent cohort of 90 treatment-naïve prostate cancer patients (r=0.74, P<0.0001). Metabolic profiling of prostate cancer cell lines revealed that PSMA-high cells exhibit pronounced fatty acid oxidation dependency for mitochondrial respiration. Pharmacological inhibition of ATGL using NG-497 selectively impaired the viability of PSMA-high, metabolically inflexible LNCaP cells while metabolically flexible 22RV1 cells showed relative resistance. Our findings establish ATGL-driven lipolysis as a targetable metabolic vulnerability in PSMA- and ATGL-expressing prostate cancer, providing a biomarker-driven therapeutic strategy for metabolically vulnerable tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303504 | GEO | 2026/08/01

REPOSITORIES: GEO