Integrative methylation and transcriptomic analysis reveals key genes linking cellular senescence and metabolic reprogramming in colorectal liver metastasis.

Colorectal liver metastasis (CRLM) remains lethal, and the convergence of cellular senescence with metabolic reprogramming via epigenomic rewiring is poorly understood. We integrated genome-wide DNA methylation and RNA-seq data from 10 paired primary tumors and liver metastases (GSE213402). After calling differentially methylated genes (3,399 hyper- and 9,519 hypomethylated) and differentially expressed genes (406 DEGs), we intersected them with curated senescence (n = 866) and metabolic reprogramming (n = 948) gene sets, yielding 28 differentially expressed cellular-senescence-related genes (DE-CSRGs) and 24 metabolic-reprogramming-related genes (DE-MRRGs). Machine-learning pipelines (LASSO + SVM-RFE) converged on a five-gene signature: CXCL1, SERPINE1, NDRG1, SRM and GATM, most of which are hypomethylated and over-expressed in metastases. Gene-set enrichment analysis revealed that these genes are involved in pathways such as oxidative phosphorylation, focal adhesion, complement-coagulation cascades, and PPAR signaling. Immune de-convolution revealed strong positive correlations between signature genes and immunosuppressive subsets (MDSCs, Tregs, type-1 T-helper cells; p < 0.05). Elevated IC50 values for oxaliplatin and 5-fluorouracil in metastatic samples were positively associated with NDRG1 and negatively with SRM, indicating chemo-resistance modulation. This five-gene epigenetic-transcriptomic hub identifies a molecular signature that warrants prospective validation as a potential biomarker for patient stratification and combination therapy in CRLM.