PHGDH: a metabolic switch in tumor drug resistance and a therapeutic target.

Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the de novo serine biosynthesis pathway. Aberrant PHGDH overexpression has been observed in multiple malignancies and is closely associated with tumor progression, therapeutic resistance, and poor clinical outcomes. However, a systematic understanding of PHGDH-mediated tumor therapy resistance, particularly its role in orchestrating resistance-associated signaling networks, remains limited. In this review, summarize recent advances in understanding the molecular mechanisms of PHGDH-mediated drug resistance, with a focus on its involvement in key signaling and regulatory networks. We also discuss the structural diversity, design strategies, and optimization of PHGDH inhibitors. Collectively, these insights underscore PHGDH as a promising metabolic target for developing next-generation anticancer strategies.