Glyoxalase 2 Drives D-Lactate Oncometabolite Signaling to Promote Prostate Cancer Aggressiveness via FAK/Src Activation.

Glyoxalase 2 (Glo2) is a key enzyme of the glyoxalase system that catalyzes the conversion of S-lactoylglutathione (LSG) into glutathione (GSH) and D-lactate. In prostate cancer (PCa), we previously demonstrated that the oncogenic PTEN-PI3K-AKT-mTOR-ERα signaling pathway upregulates Glo2, leading to intracellular D-lactate accumulation and enhanced cell migration, invasiveness, and expression of epithelial-to-mesenchymal transition (EMT)-associated markers. However, whether D-lactate acts as a bioactive metabolic signal contributing to tumor aggressiveness remains unclear. Here, after confirming our previous findings, we demonstrate-using Glo2 silencing, ectopic expression, pharmacological inhibitors, and exogenous D-lactate supplementation-that Glo2-dependent D-lactate accumulation promotes EMT-like plasticity, migration, and invasion in PTEN-deficient PCa cells via a functional link with FAK/Src signaling. Collectively, these results suggest that the Glo2-D-lactate axis may contribute to metabolic rewiring associated with aggressive behavior in PTEN-deficient PCa, warranting further in vivo studies to evaluate its potential as a therapeutic target to limit tumor progression.