Integrative analysis and functional validation identified palmitoylated PHGDH as a therapeutic target for colon adenocarcinoma

Colon adenocarcinoma (COAD) has high incidence and mortality with poor prognosis, creating an urgent need for novel prognostic models and therapeutic strategies. Protein palmitoylation, an important post-translational modification, exerts pivotal effects on tumorigenesis; however, its prognostic and mechanistic relevance in COAD remains unknown. This study determined palmitoylation-related prognostic biomarkers and probable therapeutic targets to treat COAD. We integrated transcriptomic datasets from the TCGA and identified prognostic genes related to palmitoylation by conducting differential expression analysis, weighted gene correlation network analysis, and Cox proportional hazards modeling using the least absolute shrinkage and selection operator (LASSO) method. Based on these genes, we established a robust risk signature and nomogram that consistently stratified COAD patients into distinct risk groups. Multi-omics profiling, including immune infiltration assessment, drug response prediction, and single-cell mapping, revealed distinct molecular and cellular programs within each risk group. In vitro and in vivo studies were conducted using the representative hub gene PHGDH to validate its function in COAD. A risk score model comprising three palmitoylation-related genes (PHGDH, LAMA2, and PBXIP1) stratified COAD patients into subgroups with distinct survival, immune infiltration, and drug sensitivity profiles. PHGDH was identified as the most dysregulated candidate. Functional studies revealed that depleting PHGDH significantly repressed cell proliferation and induced apoptosis. Critically, pharmacological inhibition of PHGDH palmitoylation markedly suppressed tumor growth in vitro and in xenograft models, indicating its feasibility as a therapeutic target for COAD. The palmitoylation-related risk model established in this study demonstrates strong prognostic predictive capability for COAD, offering a promising new clinical stratification tool. Furthermore, PHGDH was validated as a key functional target whose activity is regulated by palmitoylation, presenting a novel therapeutic opportunity for COAD treatment.