PHGDH (phosphoglycerate dehydrogenase) catalyzes the first rate-limiting step in de novo serine biosynthesis, converting 3-phosphoglycerate to 3-phosphohydroxypyruvate 1. Beyond its metabolic function, PHGDH exhibits diverse regulatory roles in cancer and neurological disorders. In hepatocellular carcinoma, PHGDH activity is enhanced through PRMT1-mediated arginine methylation at residue 236, promoting serine synthesis and tumor growth 2. This methylation is regulated by FBXO7-mediated ubiquitination of PRMT1 3. Paradoxically, heterogeneous or low PHGDH expression in breast cancer promotes metastasis through non-catalytic mechanisms involving aberrant protein glycosylation and integrin sialylation 4. PHGDH also drives immunosuppression by promoting M2 macrophage polarization via α-ketoglutarate production and mTORC1 signaling 5. In glioblastoma, PHGDH-mediated endothelial metabolism creates hypoxic, immune-hostile microenvironments that reduce CAR-T cell therapy efficacy 6. Additionally, PHGDH has a transcriptional regulatory function in Alzheimer's disease, promoting IKKα and HMGB1 expression in astrocytes, which accelerates amyloid pathology independent of its enzymatic activity 7. These findings establish PHGDH as a multifunctional protein with both metabolic and non-metabolic roles in disease pathogenesis.