PHGDH: metabolic enzyme or signaling hub? From broad-spectrum inhibition toward context-adapted therapeutic targeting.

Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the de novo serine synthesis pathway (SSP), has emerged as a context-dependent metabolic hub that integrates glycolysis, one-carbon metabolism, redox homeostasis, and epigenetic regulation. It is regulated by a multi-layered network encompassing transcriptional control, post-translational modifications, and protein homeostasis. PHGDH activity is further modulated by microenvironmental factors including the NAD+/NADH ratio, lactate, and pyruvate availability, leading to frequent decoupling of expression from enzymatic activity. Its functional duality uncovered in oncology mechanistically defines PHGDH as a pivotal regulator of cell fate. Here, we recapitulate the understanding of how PHGDH is regulated and its ever-expanding functional landscape across various pathological scenarios through ever-expanding moonlighting activities beyond being a metabolic enzyme. We also discuss the intervention of PHGDH functionality by a repertoire of natural modulators that exhibits promising efficacy, which offers new avenues for drug development, holding important clinical significance. Future studies better dissecting PHGDH biological architecture will foster the move beyond broad-spectrum modulation toward context-adapted interventions to achieve favorable therapeutic outcomes.