Serine Metabolism in Cancer Biology

Serine occupies a central node in cellular metabolism, linking glycolysis to one-carbon units, nucleotide synthesis and redox balance. In cancer cells, serine can be acquired via uptake or synthesised de novo from 3-phosphoglycerate through a three-step pathway involving PHGDH, PSAT1 and PSPH. Elevated flux through this pathway supports rapid proliferation by supplying glycine and one-carbon units for nucleotide and methyl group production, while also maintaining antioxidant defences through glutathione synthesis. Beyond biosynthesis, serine availability influences signalling programmes such as p53-mediated apoptosis and transcriptional responses to nutrient stress. Tumour cells frequently exploit serine metabolism through genetic amplification or post-translational modification of key enzymes, and by upregulating specialised transporters to satisfy heightened biosynthetic demands. Heterogeneity in serine synthesis and uptake underlies variable therapeutic vulnerabilities, making this pathway a prime target for dietary, pharmacological and precision oncology interventions.

Research from Nature Portfolio

One study has revealed that arginine methylation of PHGDH by PRMT1 at a specific residue enhances catalytic activity in hepatocellular carcinoma, driving increased serine production, reduced oxidative stress and accelerated tumour growth. Blocking this methylation event with a designed peptide reduces serine synthesis and restrains tumour progression in xenograft models. Another investigation identified major serine transporters in colorectal cancer cells by systematic silencing of solute carrier genes combined with metabolomic profiling. SLC6A14 emerged as the principal plasma-membrane importer, while SLC25A15 and SLC12A4 mediate mitochondrial and compensatory uptake. Dual targeting of these carriers impairs serine acquisition and suppresses tumour growth in vitro and in vivo, particularly when de novo synthesis is limited. A complementary approach demonstrated that small-molecule inhibition of PHGDH synergises with dietary serine and glycine restriction to limit one-carbon metabolism, impair stress-response signalling and curb tumour expansion in resistant models, underscoring the promise of combined dietary and pharmacological strategies.

Serine Metabolism in Cancer Biology publication trend

The graph below shows the total number of articles in serine metabolism in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

De novo serine synthesis: The three-enzyme pathway converting 3-phosphoglycerate into serine via PHGDH, PSAT1 and PSPH.

One-carbon metabolism: A network of reactions transferring single carbon units, derived from serine and folate, for nucleotide, amino acid and methylation reactions.

PHGDH: Phosphoglycerate dehydrogenase, the rate-limiting enzyme initiating serine biosynthesis from glycolytic intermediate 3-phosphoglycerate.

PSAT1: Phosphoserine aminotransferase 1, catalysing the conversion of phosphohydroxypyruvate to phosphoserine in serine biosynthesis.

Solute carriers (SLCs): A large family of membrane proteins mediating uptake and exchange of metabolites, including amino acids such as serine.

References

1. PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma. Nature Communications (2023).
2. Phenotypic profiling of solute carriers characterizes serine transport in cancer. Nature Metabolism (2023).
3. Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy. Nature Communications (2021).
4. Targeting PSAT1 to mitigate metastasis in tumors with p53-72Pro variant. Signal Transduction and Targeted Therapy (2023).
5. Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate. Cell Research (2023).
6. Integrative single-cell and bulk transcriptomes analyses reveals heterogeneity of serine-glycine-one-carbon metabolism with distinct prognoses and therapeutic vulnerabilities in HNSCC. International Journal of Oral Science (2024).