A Novel Predictive Model Based on Glutathione Metabolism Genes RRM2 and G6PD in Hepatocellular Carcinoma

Glutathione (GSH) metabolism is closely associated with tumor behavior in hepatocellular carcinoma (HCC). HCC is the third fatality reason and the sixth incidence rank in global tumor ranking. Our study explored the connection between glutathione metabolism genes (GMGs) expression and HCC progression and prognosis.

We obtained seven differentially expressed genes (DEGs) by analyzing GMGs dataset in HCC and the TCGA-LIHC cohort. Utilizing LASSO Cox analysis, we developed a predictive model based on 2-GMGs: Ribonucleotide reductase regulatory subunit M2 (RRM2) and glucose-6-phosphate dehydrogenase (G6PD). The model was apprized with the SHapley Additive exPlanations (SHAP). The predictive ability of the model was rigorously validated through prognostic stratification, univariable and multivariable Cox regression, and nomogram construction. We anticipated chemotherapy sensitivity using the GDSC database and used GEPIA and TIMER to examine the correlations with 2-GMGs expression and cellular immune-associated markers. This study also detects the impact of RRM2 and G6PD expression on HCC patient survival through immunohistochemistry.

A prognostic model and nomogram composed of 2-GMGs provided an accurate prognostic for HCC patients. The median risk score as a dividing criterion was used to classify into low and high-risk groups. A positive outcome for the lowest-risk group was achieved by Kaplan-Meier curves. Moreover, the risk score was verified as an independable predictive indicator by multifactorial and unifactorial Cox regression analyses. Notable disparities between the two groups regarding the infiltration of different immune cell subtypes, tumor mutation burden (TMB) and sensitivity to chemotherapeutic subtypes were observed. Finally, immunohistochemical indicated that increased RRM2 and G6PD expression and decreased viability of HCC patients.

Our findings exposit that the higher 2-GMGs expression and the worse progression and prognosis of HCC. The SHAP approach was employed to elucidate the 2-GMGs model, enhancing its utility for clinicians.