Objective To investigate the expression pattern, prognostic significance, and underlying molecular mechanisms of mutY homolog (MUTYH) in hepatocellular carcinoma (HCC), and to evaluate its clinical potential as a novel biomarker and therapeutic target.

Methods The differential expression of MUTYH between HCC and normal tissues was compared using the TCGA and GEO databases. Associations with clinicopathological parameters, TP53 mutation status, diagnostic efficacy of alpha-fetoprotein (AFP), and sorafenib resistance were analyzed. Prognostic impact was evaluated using the Kaplan-Meier method with the log-rank test, and univariate and multivariate Cox proportional hazards regression models were used to verify its independent prognostic value. Molecular mechanisms were explored through GO, KEGG, and GSEA enrichment analyses as well as protein-protein interaction (PPI) network construction. The correlations of MUTYH with immune cell infiltration and the immunotherapeutic efficacy of immune checkpoint inhibitors were assessed using the CIBERSORT algorithm and the BEST database. Quantitative real-time PCR (qPCR) was performed to validate the expression differences of MUTYH and its core interacting molecules between HCC and normal tissues.

Results MUTYH was significantly upregulated in HCC (P < 0.05), clinical sample tests have confirmed that it can serve as a biomarker for diagnosing HCC (area under the curve AUC = 0.824, 95% CI: 0.762-0.886, P < 0.001), its diagnostic value remains high even in the HCC subgroup with low AFP expression (GSE25097, AUC = 0.716, P < 0.001; GSE63898, AUC = 0.624, P < 0.001). High MUTYH expression correlated with sorafenib resistance (P < 0.05) and was an independent risk factor for poor overall survival (hazard ratio HR = 1.92, P < 0.05). Mechanistically, MUTYH was positively associated with apurinic/apyrimidinic endonuclease 1 (APEX1) (r = 0.83, P < 0.05), potentially facilitating G₁/S transition by modulating cyclin-dependent kinase 4, cyclin-dependent kinase 7, and cyclin E2. Immune analysis identified MUTYH as a predictor for anti-PD-1/PD-L1 response (IMvigor210 AUC = 0.637; Cho2020 AUC = 0.782), though no association was found with anti-CTLA-4 therapy.

Conclusion MUTYH is significantly overexpressed in HCC and may promote HCC progression by regulating APEX1 and key cell cycle molecules. Compared with the conventional marker AFP, MUTYH demonstrates superior diagnostic and prognostic evaluation efficacy and is associated with anti-PD-1/PD-L1 therapeutic response and sorafenib resistance. Overall, MUTYH has potential as a novel biomarker and therapeutic target for HCC.