【Abstract】 Objective To investigate the characteristics of liver injury in the Lieber-DeCarli alcoholic liver disease (ALD) mouse model and to analyze its transcriptomic profile. Methods Eighteen male C57BL/6J mice were randomly divided into an alcohol-fed group (n=10) and a control group (n=8). The alcohol-fed group received a Lieber-DeCarli ethanol diet, starting with an adaptive one-week phase using incremental concentrations of ethanol (10∽57.3 ml/L) and followed by two weeks at a 57.3 ml/L concentration of 95% ethanol, totaling three weeks. The control group was provided with an isocaloric control diet for three weeks. At the end of the study, mice were sacrificed to collect serum and liver tissue samples. Serum liver function markers (ALT, AST), hepatic lipids (TC, TG), reduced glutathione (GSH), total superoxide dismutase (T-SOD), and malondialdehyde (MDA) were measured using biochemical assays. Levels of inflammatory cytokines (IL-6, IL-10, TNF-α, TGF-β1) in liver tissue were assessed by ELISA. Histopathological changes in liver tissue were examined using hematoxylin-eosin (HE) and Oil Red O staining. RNA sequencing (RNA-seq) was used to identify differentially expressed genes (DEGs) in liver tissue, followed by Gene Ontology (GO) and KEGG pathway enrichment analyses. Selected DEGs were validated by quantitative real-time PCR (qRT-PCR).Results Compared to the control group, the alcohol-fed group exhibited significant weight loss (P < 0.01), elevated serum AST and ALT levels (P < 0.01), increased hepatic TC, TG, and MDA (P < 0.05), and decreased GSH and SOD (P < 0.05). Histopathology showed disrupted hepatic lobular structure with macrovesicular steatosis, ballooning degeneration, and a significant increase in lipid droplets in liver tissue. A total of 2,063 DEGs (1,236 upregulated and 827 downregulated) were identified (|log2FC| > 1, q < 0.05), predominantly enriched in pathways such as xenobiotic metabolism via cytochrome P450, cytokine-cytokine receptor interaction, chemokine signaling, steroid hormone biosynthesis, glutathione metabolism, and retinol metabolism. Key upregulated genes included Mmp12, Gstm3, Cyp2a22, Lcn2, Plin4, Cyp2a4, Acot2, Tubb2a, Mgst3, and Ccl6, while downregulated genes included Serpina1e, Acmsd, Mup3, Cyp7a1, Ces3b, Serpina3k, C8b, Mup8, Mup2, and C8a, with consistent trends confirmed by qRT-PCR (P < 0.05).Conclusion The primary pathological mechanisms underlying alcoholic liver injury involve pathways related to xenobiotic metabolism via cytochrome P450, cytokine-cytokine receptor interaction, chemokine signaling, glutathione metabolism, and retinol metabolism.