Multi-Omics Analysis and Real-World Data Validation of Serine Metabolism-Related Genes in Colorectal Cancer

Serine metabolism plays a pivotal role in cancer progression by supporting essential biosynthetic pathways and energy production. Exploring the intricacies of serine metabolism in cancer may uncover novel therapeutic opportunities. This study presents a comprehensive pan-cancer analysis of serine metabolism-related genes (SMGs), with a particular emphasis on colorectal cancer (CRC), to elucidate their expression patterns, genetic alterations and clinical significance. We performed a pan-cancer analysis of SMGs using integrating transcriptomic, genomic and epigenetic data from TCGA and GTEx databases. For CRC, we performed in-depth analyses comparing expression patterns between tumour and normal tissues, examining prognostic significance and exploring associations with the tumour microenvironment (TME). The distribution patterns of SMGs within the TME were further investigated using single-cell RNA sequencing and immunohistochemistry. Key SMGs, including PHGDH, SLC1A5 and SLC38A2, were validated in two independent real-world cohorts of CRC. Pan-cancer analysis revealed that SMGs are differentially expressed across tumour types, with their dysregulation associated with copy number alterations and epigenetic modifications. In CRC, aberrant SMG expression is significantly associated with clinical outcomes, key signalling pathways and the TME. Notably, PHGDH was consistently upregulated in CRC and associated with poor prognosis, while SLC1A5 emerged as a potential biomarker for liver metastasis. This study underscores the importance of SMGs, particularly PHGDH, SLC1A5 and SLC38A2, in CRC progression and prognosis. Our findings offer valuable insights into SMGs as a potential therapeutic target and provide a foundation for developing personalised metabolic interventions in CRC.