非酒精性脂肪性肝病的转录组学特征及关键分子解析

Objective  Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disorder worldwide, with non-alcoholic steatohepatitis (NASH) carrying a high risk of progression to fibrosis, cirrhosis, and hepatocellular carcinoma. This study aimed to identify key molecular events underlying the transition from non-alcoholic fatty liver(NAFL) to NASH by integrating multi-cohort transcriptomic data, thereby providing potential early biomarkers and therapeutic targets. Methods  Four liver tissue RNA-seq datasets from the GEO database (total n=293) were collected and integratd. After quality control and batch correction, 286 high-quality samples were retained (HC=46, NAFL=70, NASH=170). Differentially expressed genes(DEGs) were identified using three analytical pipelines (edgeR, limma-voom, and DESeq2). Functional enrichment was performed through GSEA, GO, and KEGG analyses, followed by consensus pathway screening and validation of pathway activity using single-sample GSEA (ssGSEA). Results  NAFL showed mild disturbances in metabolic homeostasis and low-grade inflammation. In contrast, NASH displayed pronounced activation of pathways related to inflammation, immune response, cell cycle regulation, and extracellular matrix (ECM) remodeling. Comparison of NASH and NAFL highlighted pronounced cell cycle dysregulation, enhanced inflammation, and ECM-related changes. ssGSEA verified progressive activation of E2F targets, G2/M checkpoint, and TNF-α/NF-κB signaling along the disease spectrum. Conclusion   The progression from NAFL to NASH involves a gradual shift from metabolic imbalance to inflammation, cell cycle dysregulation, and ECM remodeling. This study delineates the transcriptomic landscape of NAFLD progression and provides a valuable resource for mechanistic insights and identification of potential therapeutic targets.