Objective To screen and validate targeted therapeutic agents for key differentially expressed genes (DEGs) related to metabolism in non-alcoholic steatohepatitis (NASH), in order to provide a reference for the development of new drugs for NASH. Methods The NASH gene expression profiles GSE164760 and GSE63067 datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using R software, and GO molecular function and KEGG signaling pathway analyses were performed. The DEGs associated with NASH and metabolic genes were intersected to screen NASH metabolic key DEGs using LASSO regression model and SVM-RFE algorithm. Targeted therapeutic agents for NASH metabolic key DEGs were identified using the Comparative Toxicogenomics Database (CTD), Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and PubMed database. Molecular docking was conducted using Autodock4 software to verify the targeted relationship between the obtained therapeutic agents and NASH metabolic key DEGs. The effect of naringenin, a NASH metabolic key DEGs targeted therapeutic agent, on the content of intracellular lipid droplets in NASH cells was observed using Oil Red 〇 staining. The effect of naringenin on the expression of NASH metabolic key DEGs within NASH cells was observed using real-time quantitative RT-qPCR. Results A total of 336 DEGs were identified, which were mainly involved in fatty acid metabolism, protein targeting, small molecule degradation metabolism, the biosynthesis of auxiliary factors, bile secretion, and peroxisomes, and other signaling pathways. The NASH metabolic key DEGs were identified as SLCO1B1, SCD, and ACAT1 genes. Four compounds, naringenin, cyclosporin, abrine, and chenodeoxycholic acid, were found to target ACAT1, SCD, and SLCO1B1. Molecular docking results indicated that naringenin, cyclosporin, abrine, and chenodeoxycholic acid had good molecular binding activity with ACAT1, SCD, and SLCO1B1 genes, suggesting a targeted relationship. Cell experiments demonstrated that the targeted therapeutic agent naringenin could decrease the content of intracellular lipid droplets in NASH cells and influence the expression of ACAT1, SCD, and SLCO1B1 genes within NASH cells. Conclusion The targeted therapeutic agents for key DEGs related to metabolism in NASH are naringenin, cyclosporin, abrine, and chenodeoxycholic acid, which are validated by molecular docking and cell experiments. [ABSTRACT FROM AUTHOR]