Identification of an Autophagy-Related Gene Signature Driving the Transition from NASH to Hepatocellular Carcinoma

Background: The rising incidence of non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) presents a significant clinical challenge. While dysregulated autophagy is known to parallel the metabolic-to-malignant transition in the liver, the specific autophagy-related gene (ARG) signatures driving this progression remain poorly defined. This study aims to identify key ARGs that mediate the transition from NASH to HCC and evaluate their prognostic significance. Methods: Transcriptomic data from the GSE164760 dataset were analyzed to identify differentially expressed genes (DEGs) between NASH liver tissues (n=74) and NASH-HCC samples (n=53). These DEGs were intersected with the Human Autophagy Database (HADb) to isolate autophagy-related DEGs (ARDEGs). Protein-protein interaction (PPI) networks, Spearman correlation, and functional enrichment analyses (GO/KEGG) were performed to elucidate molecular mechanisms. Clinical validation and survival analysis were conducted using the Kaplan-Meier Plotter database based on the TCGA-LIHC cohort (n=364). Results: A total of 19 ARDEGs (6 upregulated, 13 downregulated) were identified as the core signature of the NASH-to-HCC transition. Functional enrichment revealed that these genes are predominantly involved in the mTOR signaling pathway, mitophagy, and choline metabolism in cancer. Network analysis identified HIF1A and MYC as critical bridging nodes, while CDKN2A and SQSTM1 emerged as the top-ranking hub genes. Survival analysis demonstrated that low expression of CDKN2A (HR=0.52, P <0.001) and SQSTM1 (HR=0.61, P <0.01), alongside high expression of RHEB and CASP1 , were significantly associated with poor overall survival in liver cancer patients. Conclusion: Our study identifies a robust 19-gene autophagy-related signature that characterizes the malignant evolution of NASH. The HIF1A/MYC/SQSTM1 axis appears to be a central regulatory hub linking metabolic hypoxia to autophagic exhaustion and tumor progression. These ARDEGs represent potential biomarkers for early detection and therapeutic targets for intercepting NASH-driven hepatocarcinogenesis.