Phgdh, or Phosphoglycerate Dehydrogenase, is a key enzyme in the serine biosynthesis pathway, catalyzing the conversion of 3-phosphoglycerate to 3-phosphohydroxypyruvate. Serine is essential for DNA synthesis through one-carbon unit generation and for antioxidant production in cancer cells. This pathway and Phgdh are thus of great biological importance in cellular proliferation and stress prevention [6].

Knock-down of Phgdh in bladder cancer cells promoted ferroptosis and decreased cell proliferation, while also downregulating SLC7A11 expression. Mechanistically, Phgdh binds to PCBP2, inhibiting its ubiquitination degradation, and PCBP2 in turn stabilizes SLC7A11 mRNA [1]. In breast cancer, loss of Phgdh potentiated metastatic dissemination, with low Phgdh expression in primary tumors associated with decreased metastasis-free survival. Circulating tumour cells and early metastatic lesions were enriched with Phgdh-low cancer cells, and silencing Phgdh in primary tumours increased metastasis formation [2]. In tumor-associated macrophages, loss of Phgdh disrupted cellular metabolism and mitochondrial respiration essential for immunosuppressive macrophages, leading to attenuated tumor growth, reduced infiltration, and a phenotypic shift [3]. In endothelial cells of glioblastoma, genetic ablation of Phgdh pruned over-sprouting vasculature, abrogated intratumoral hypoxia, and improved T-cell infiltration [4]. In hepatocellular carcinoma, blocking Phgdh methylation with a peptide inhibited serine synthesis and restrained tumor growth [5]. In HCC, inactivation of Phgdh through RNAi knockdown or Nuclease technology knockout paralyzed the serine synthesis pathway, elevated ROS levels, and induced apoptosis upon sorafenib treatment. The Phgdh inhibitor NCT-503 worked synergistically with sorafenib to abolish HCC growth in vivo [7].

In conclusion, Phgdh plays a crucial role in various biological processes and disease conditions. Through gene-knockout and related models, its functions in promoting cancer cell survival, metastasis, and immunosuppression have been revealed. Understanding Phgdh's role is important for developing therapeutic strategies against cancers such as bladder, breast, glioblastoma, and hepatocellular carcinoma, as well as for countering immunosuppression in the tumor microenvironment.