Phgdh, also known as PhosphoGlycerol Dehydrogenase, is the first rate-limiting enzyme in the serine biosynthesis pathway, catalyzing the conversion of 3-phosphoglycerate to 3-phosphohydroxypyruvate. Serine synthesis is crucial for macromolecule synthesis, neutralizing oxidative stress, and regulating methylation reactions. This pathway is associated with various biological processes such as cell proliferation, metastasis, and immune-related functions [1,3,4,6].

In bladder cancer, knockdown of Phgdh promoted ferroptosis and decreased cancer cell proliferation while downregulating SLC7A11 expression. Phgdh interacts with 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. Mechanistically, loss of the interaction between Phgdh and phosphofructokinase activated the hexosamine-sialic acid pathway, leading to aberrant protein glycosylation and increased cell migration [2]. In hepatocellular carcinoma, PRMT1-mediated methylation of Phgdh at arginine 236 enhanced its catalytic activity, promoting serine synthesis and tumor growth. Blocking this methylation inhibited serine synthesis and restrained tumor growth [4]. In glioblastoma, genetic ablation of Phgdh in endothelial cells pruned over-sprouting vasculature, abrogated intratumoral hypoxia, and improved T-cell infiltration. In HCC, inactivation of Phgdh reduced the production of key metabolites, elevated ROS levels, and induced apoptosis upon Sorafenib treatment. The Phgdh inhibitor NCT-503 worked synergistically with Sorafenib to abolish HCC growth. In pre-clinical models of brain metastasis, genetic suppression and pharmacologic inhibition of Phgdh attenuated brain metastasis but not extracranial tumor growth [5,7,8].

In conclusion, Phgdh plays a vital role in serine synthesis, which impacts multiple biological processes and disease conditions. Gene knockout and other loss-of-function models have revealed its significance in cancer metastasis, tumor growth, and response to therapies in various cancers, highlighting its potential as a therapeutic target [1-2,4-5,9-10].