Nobiletin Ameliorates Alcohol-Induced Liver Injury via Modulation of the Gut-Liver Axis

Alcoholic liver disease (ALD) is a significant health burden with limited therapeutic options. This study aimed to elucidate the protective mechanisms of nobiletin (NOB) against alcohol-induced liver injury in mice, focusing on the gut-liver axis. After a 7-day high-dose NOB intervention, treated mice showed a significant increase in body weight (P < 0.05) and marked improvements in key serum parameters, including 25% reduced aspartate aminotransferase (AST), 45% decreased low-density lipoprotein cholesterol (LDL-C), 25% suppressed interleukin-6 (IL-6) and 10% reduced tumor necrosis factor-α (TNF-α) relative to the alcohol-induced model group. Untargeted metabolomics analysis revealed that NOB remodeled glycerophospholipid metabolism, specifically upregulating phosphatidylcholine (PC) and phosphatidylethanolamine (PE) while suppressing lysophospholipids (LysoPC/LysoPE). Concurrently, NOB enhanced intestinal barrier integrity via upregulation of the tight junction protein ZO-1 and Occludin, Furthermore, it modulated gut microbiota composition by enriching beneficial probiotics such as Lactobacillus. In liver tissue, NOB activated the Nrf2 antioxidant pathway, increasing enzymes (SOD, CAT, GSH) and reducing malondialdehyde (MDA), while simultaneously inhibiting the NF-κB pathway and its downstream pro-inflammatory cytokines (TNF-α, IL-1β). Spearman correlation analysis further linked specific microbial shifts (Lactobacillus murinus) with the observed serum metabolic changes (PC, PE). Collectively, these findings demonstrate that NOB mitigates alcoholic liver injury through multi-pathway involvement of the “intestinal flora–glycerophospholipid metabolism–hepatic inflammation” axis, presenting a novel therapeutic candidate for ALD that warrants further clinical investigation.