Comprehensive Multi-Omics Characterization of CYP2R1 as a Diagnostic and Functional Biomarker in Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) remains a major cause of cancer mortality worldwide, yet reliable molecular biomarkers for early diagnosis and prognosis are limited. The cytochrome P450 (CYP) enzyme superfamily plays central roles in hepatic metabolism and tumor biology, but its global dysregulation in HCC has not been comprehensively defined. Methods: Here, we systematically analyzed 57 CYP genes across multi-cohort transcriptomic datasets (GepLiver, TCGA-LIHC, HCCDB2.0) to delineate their diagnostic, prognostic, and functional significance. Results: CYP2R1 emerged as a consistently upregulated and clinically relevant member, showing excellent diagnostic accuracy (AUC = 0.95, 95% CI: 0.94–0.98, p < 0.001) and strong overexpression validated across independent cohorts and spatial transcriptomics. Prognostic modeling identified CYP2C9 (favorable) and CYP26B1 (unfavorable) as independent survival markers. Functional enrichment analyses revealed that high CYP2R1 expression was associated with activation of DNA repair and replication pathways (NES = 1.31, adjusted p = 1.05 × 10−5) and with co-expression of core repair genes such as POLA2, LIG1, and PCNA. Moreover, CYP2R1 correlated with myeloid-derived suppressor cell infiltration, suggesting an immunosuppressive phenotype. Conclusions: These findings establish CYP2R1 as a novel metabolic and immunogenomic biomarker in HCC, linking hepatic metabolism, genomic maintenance, and tumor immune modulation.