Coffee is one of the most widely consumed beverages worldwide, and numerous studies have reported its health-related benefits. In this study, the impact of caffeine, a major bioactive constituent of coffee, on mouse liver function was investigated using network-based analysis and gene ontology enrichment approaches. Gene expression data from the GSE53131 dataset were retrieved from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) between mice fed caffeinated coffee and those receiving decaffeinated coffee were identified and further analyzed through protein–protein interaction (PPI) network construction and gene ontology enrichment. Data analysis was performed using the STRING database and Cytoscape software. Caffeine-associated effects on liver function were reflected in distinct hepatic gene expression patterns between mice consuming caffeinated versus decaffeinated coffee. Key discriminative genes—including Acly, Acss2, Acat2, Akr1d1, Elovl2, Ehhadh, Fdps, Fasn, Hmgcr, Gsta3, Ldlr, Lss, Mmab, Mvk, Mvd, Nsdhl, Prodh, Rdh11, and Thrsp—were primarily involved in lipid metabolism and cholesterol biosynthetic pathways. Overall, transcriptomic analysis of mouse liver revealed that consumption of caffeinated coffee markedly influences hepatic lipid metabolism compared with decaffeinated coffee intake. Based on these findings, caffeine may play a potential protective role in the prevention of hepatic metabolic disorders.
