Colorectal cancer (CRC) remains a critical global health challenge, ranking second in cancer-related mortality and third in cancer incidence as of 2018, with risk increasing with age. Addressing its rising burden requires early diagnosis, prognostic biomarkers, and effective therapeutic strategies. Emerging evidence suggests that calorie restriction may mitigate aging-related functional decline and influence CRC progression, yet the molecular markers and mechanisms remain poorly understood. In this study, we analyzed the GSE24432 dataset, using multiple computational databases to screen differentially expressed genes (DEGs) associated with calorie restriction in CRC. Functional annotations, including Gene Ontology (GO), KEGG pathway analysis, and gene set enrichment analysis (GSEA), were undertaken to explore potential underlying mechanisms and pathways in CRC pathogenesis. Kaplan Meier and Cox proportional hazards regression analyses were conducted to establish the diagnostic and prognostic significance of the hub genes. The validation test was conducted via multiple databases. Our investigation identified 50 DEGs, using the cutoff criteria, p. adj <
0.05, |log2FC|>
0.3. GO and functional analysis results revealed extensive crosstalk of cellular and molecular components and pathways associated with mRNA and ribosome biogenesis, AMPK signaling, and p53 signaling pathway following calorie restriction. To understand how these DEGs drive biological reactions, we sorted the genes according to gene score >
3 and GO term >
3 and obtained 14 DEGs most relevant to the GO terms. Further analysis with GO CHORD showed that most genes are enriched in ribosome biogenesis and protein synthesis. Gene set enrichment analysis (GSEA) revealed the involvement of the hub genes in several hallmarks, such as tissue invasion and metastasis (p <
0.001), tumor-promoting inflammation (p <
0.001), resisting cell death (p <
0.01), and replicative immortality (p <
0.05). Survival analysis showed that higher expression of 7 hub genes, CDKN2A (p <
0.05), RPL9 (p <
0.02), TUBB6 (p <
0.01), and RPS15A (p <
0.01), and lower expression of CDKN1B (p <
0.01), NPM1 (p <
0.01), and RALA (p <
0.01), correlated to shorter survival of colon cancer. However, cross-reference of these genes revealed that calorie restriction decreased the expressions of CDKN2A and TUBB6 while CDKN1B and NPM1 were increased (p <
0.05). Several validation tests from multiple databases showed that high CDKN2A is associated with shorter overall survival rates, indicating CDKN2A is a therapeutic target and could serve as a more reliable biomarker for CRC prognosis. These findings could potentially facilitate the development of precision-based energy restriction interventions for CRC management, offering promising prospects for targeted therapeutic strategies for CRC patients.