非酒精性脂肪性肝病的转录组学特征及关键分子解析OA

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.