PHGDH in cancer: a narrative review of its functions beyond serine metabolism.

BACKGROUND AND OBJECTIVE: Metabolic reprogramming represents a fundamental characteristic of cancer, with dysregulation of serine metabolism being increasingly recognized as a critical contributor to tumor transformation and progression. Cancer cells acquire serine through two major pathways: exogenous uptake from food and endogenous synthesis via the de novo serine biosynthesis pathway (SSP). The first and the committed step of SSP is catalyzed by 3-phosphoglycerate dehydrogenase (PHGDH). Since the discovery of PHGDH amplification in certain malignancies, extensive research has established its crucial function in promoting oncogenesis primarily through enhancing serine bioavailability. Intriguingly, many tumors maintain elevated PHGDH expression and activity even when extracellular serine is abundant, suggesting serine-independent oncogenic functions. This study aimed to provide an overview of the main processes and regulatory mechanism of serine metabolism that centres on PHGDH, summarize the emerging non-canonical functions of PHGDH in cancer and the latest advances in PHGDH-targeted cancer therapy. METHODS: We comprehensively reviewed the current literature on PHGDH in cancer by searching PubMed and Web of Science for English-language publications available up to February 2026. The evidence was critically synthesized to summarize the regulatory mechanisms, emerging non-canonical functions, and therapeutic implications of PHGDH. KEY CONTENT AND FINDINGS: We summarize the metabolic functions and regulatory mechanisms governing PHGDH expression and activity in cancer and comprehensively review its recently identified non-canonical functions beyond serine biosynthesis. Emerging evidence demonstrates that PHGDH exerts diverse metabolism-independent activities, including regulation of gene transcription, RNA metabolism and protein interactions, thereby contributing to tumor progression, immune modulation, and therapeutic responses. We further discuss the current landscape of PHGDH-targeted therapeutic strategies, including catalytic inhibitors and emerging approaches aimed at disrupting its non-metabolic functions, together with their opportunities and current limitations. CONCLUSIONS: PHGDH is not only a metabolic enzyme but also a multifunctional regulator of tumor biology. Recognition of its non-canonical activities substantially expands our understanding of serine metabolism in cancer and provides new perspectives for precision oncology. Future studies should clarify the molecular mechanisms governing PHGDH's context-dependent functions, define its interaction networks and subcellular regulation, and facilitate the development of next-generation therapeutic strategies targeting both its metabolic and non-metabolic activities.