Modulation of the Gut–Liver Axis and Nrf2/HO-1-Mediated Antioxidant Defense by Styela plicata Extract Against Alcoholic Liver Injury

Styela plicata, an edible ascidian rich in diverse bioactive constituents, represents a promising source of marine natural products for therapeutic discovery. Here, bioactive components from a 95% ethanol extract of S. plicata (ESP) were characterized by HPLC-MS/MS, showing that the major constituents were oxygenated small molecules dominated by fatty acyls and carboxylic acid derivatives. In a mouse model of alcohol-induced liver injury, H-ESP treatment (300 mg/kg) significantly reduced serum levels of AST, ALT, and TG (p < 0.01), while effectively ameliorating pathological changes in liver tissue, reducing lipid accumulation and inflammatory responses. Transcriptome sequencing (H-ESP vs. model group) identified 1097 differentially expressed genes (172 upregulated and 925 downregulated), and KEGG analysis highlighted significant enrichment of the Toll-like receptor signaling pathway. ESP modulated hepatic metabolite expression, suppressed inflammation via TLR-4/NF-κB pathway inhibition, and boosted antioxidant defenses by activating Nrf2/HO-1 signaling, which was further confirmed by RT-qPCR and immunohistochemistry. ESP increased intestinal SCFAs (acetate, propionate, isobutyrate; p < 0.05), improved α-diversity and the Firmicutes/Bacteroidetes ratio, reversed shifts in Lactobacillus and Bifidobacterium, and partly restored Odoribacter, supporting a gut–liver axis mechanism. Overall, these findings indicate that ESP exerts hepatoprotective effects by modulating the gut–liver axis, and they provide insights for developing natural therapeutics against alcoholic liver disease.