Evaluating the Role of Glutathione Reductase in Aspartame-Induced Liver Hepatocellular Carcinoma : A Molecular Network and Prognostic Approach

Sun, Wenhui and Huo, Siyan and Li, Shitian and Yang, Daifeng and Wei, Changsheng and Zheng, Jieting and Cai, Shanshan (2025) Evaluating the Role of Glutathione Reductase in Aspartame-Induced Liver Hepatocellular Carcinoma : A Molecular Network and Prognostic Approach. Toxicology Letters: 111748. ISSN 0378-4274 (In Press)

Abstract

This study aims to elucidate the molecular mechanisms underlying aspartame-associated liver hepatocellular carcinoma (LIHC) by identifying glutathione reductase (GSR) as a key molecular target. Through a combination of network toxicology analysis and Mendelian randomization, GSR was implicated as a critical protein involved in the pathogenesis of aspartame-associated LIHC. Functional annotation using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that GSR is predominantly involved in energy metabolism, particularly lipid metabolism and glycolysis, both of which are central to tumorigenesis in LIHC. Elevated GSR expression was observed in LIHC tumor tissues, correlating with poor clinical outcomes including reduced overall survival (OS) and recurrence-free survival (RFS). Furthermore, genetic analyses revealed significant alterations in GSR, including mutations and copy number variations, in various cancer types, with specific relevance to immune regulatory gene networks. Molecular dynamics simulations demonstrated a robust binding affinity between aspartame and GSR, with favorable binding interactions, suggesting a stable protein-ligand complex. Additionally, functional assays confirmed that GSR modulates tumor cell proliferation via regulation of glycolytic enzyme activity, indicating its pivotal role in metabolic reprogramming during LIHC progression. These findings collectively highlight GSR as a promising biomarker and therapeutic target in the context of aspartame-associated hepatocellular carcinoma, with implications for targeted intervention in cancer treatment.