Mitochondrial metabolism and succinylation-related gene signatures for predicting prognosis and drug resistance in colon adenocarcinoma.

BACKGROUND

Colon adenocarcinoma (COAD) has high incidence and mortality but lacks reliable molecular biomarkers for prognosis and individualized therapy. Mitochondrial metabolic reprogramming and succinylation are closely implicated in COAD progression, yet their synergistic mechanism remains unclear. This study aimed to analyze mitochondrial metabolism and succinylation-related gene (MMSRG) signatures, identify key biomarkers for COAD prognosis and drug resistance, and establish a robust prognostic model.

METHODS

We retrieved 615 succinylation-related and 14,207 mitochondrial metabolism-related genes from GeneCards. Differentially-expressed MMSRGs were identified in the TCGA-COAD dataset (524 samples). A prognostic model was constructed using univariate/multivariate Cox and LASSO regression, and validated externally in GEO GSE38832. Functional enrichment, immune infiltration, drug sensitivity, single-cell sequencing (GSE231559), and qRT-PCR analyses were performed to explore hub gene functions and clinical value.

RESULTS

A total of 144 differentially expressed MMSRGs were identified, and a two-hub-gene (MC1R, H2AC6) optimal prognostic index for survival-related variable (OPISV) model was established. Both genes were independent prognostic factors for COAD. The model achieved a 3-year time-dependent ROC AUC of 0.665 with good robustness in internal and external validation. MMSRGs were mainly enriched in protein heterodimerization and neutrophil extracellular trap formation. The low-risk group showed increased activated memory CD4 T-cell infiltration and higher chemotherapeutic and targeted drug sensitivity. Hub gene expression patterns were consistent across single-cell sequencing and qRT-PCR.

CONCLUSION

MMSRG signatures are closely associated with COAD prognosis, immune infiltration, and drug resistance. The OPISV model represents a novel biomarker for COAD prognosis and individualized treatment, providing theoretical and experimental support for COAD precision medicine.