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Zhiwei Huang,1,* Jiatong Chen,1,* Shenglu Liu,1 Xin Xiang,2 Yang Long,3 Peng Tan,1,4 Wenguang Fu1,4 1Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Department of General Surgery, The First People’s Hospital of Neijiang, Neijiang, 641000, People’s Republic of China; 3Department of Endocrinology and Metabolism, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 4Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, Academician (Expert) Workstation of Sichuan Province, Department of General Surgery (Hepatopancreatobiliary surgery), The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng Tan; Wenguang Fu, Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, People’s Republic of China, Email tanpeng@swmu.edu.cn; fuwg@swmu.edu.cnBackground: Nonalcoholic steatohepatitis (NASH) has recently garnered increased attention due to immune infiltration. However, the role of membrane-associated protein 17 (MAP17) in NASH remains unclear, which prompted this study to explore its relationship with immune infiltration and its regulatory mechanisms.Methods: We employed weighted correlation network analysis (WGCNA) to construct a gene co-expression network aimed at identifying key genes associated with NASH progression. Our further analyses included differential expression evaluation, protein-protein interaction (PPI) network analysis, and Venn diagram analysis to discover novel targets. The CIBERSORT algorithm assessed the correlation between MAP17 and immune cell infiltration within the tumor microenvironment (TME), while the TIDE algorithm predicted responses to immunotherapy. Additionally, we conducted gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) to elucidate the mechanisms by which MAP17 operates. The expression of MAP17 was validated using liver tissues obtained from NASH patients and mice with diet-induced NASH or CCl4-induced liver fibrosis.Results: Our findings identified MAP17 as a novel target in the progression of NASH. Correlation analyses demonstrated a positive association between MAP17 and M1 macrophage infiltration, as well as a negative association with M2 infiltration. TIDE results positioned MAP17 as a potential biomarker for predicting responses to immune checkpoint blockade. Mechanistic studies revealed that MAP17 induced oxidative stress, which subsequently activated the p53, PI3K-AKT, and Wnt signaling pathways. Validation analyses confirmed that MAP17 levels significantly increased in liver tissues of mice with diet-induced NASH or CCl4-induced liver fibrosis, as well as in NASH patients.Conclusion: MAP17 is a novel biomarker linked to macrophage infiltration and immunotherapy responses in NASH patients. The oxidative stress induced by MAP17 activates the p53, PI3K-AKT, and Wnt pathways, all of which contribute to the progression of NASH.Keywords: NASH, MAP17, macrophage infiltration, immunotherapy response, oxidative stress |
