- EtOH plus GalN mouse model reproduced advanced ALD features: acute liver injury, sustained inflammation, pro-fibrotic gene induction, and impaired regeneration.
- Resolvin D1 markedly reduced pathology: lowered plasma endotoxin and ALT, limited hepatic necrosis and neutrophil infiltration.
- RvD1 decreased hepatic IL-6 early and IFN-gamma later, attenuated pro-fibrotic gene expression, and improved hepatocyte proliferation and albumin.
Hepatol Commun. 2026 Aug 28;10(9):e1039. doi: 10.1097/HC9.0000000000001039. eCollection 2026 Sep 1.
ABSTRACT
BACKGROUND: Alcohol-associated liver disease (ALD) is a major global health condition characterized by inflammation, hepatocellular injury, fibrosis, and impaired liver regeneration. To capture key features of severe ALD, we employed a murine model combining ethanol (EtOH) exposure with galactosamine (GalN), a hepatotoxic agent that sensitizes the liver to endotoxin-induced injury. Using this model, we evaluated the therapeutic efficacy of resolvin D1 (RvD1), a lipid mediator with potent anti-inflammatory and tissue-protective actions.
METHODS: C57BL/6J male mice were fed 5% EtOH-containing liquid diet for 10 days and administered GalN (500 mg/kg, i.p.) on days 9, 10, and 11, followed by a single EtOH binge (5 g/kg) on day 11. A separate cohort also received RvD1 (500 ng/mouse, days 7-12) as a therapy. Markers of endotoxemia, liver injury, inflammation, fibrosis, and regeneration were evaluated at 9 and 48 hours after the binge.
RESULTS: The EtOH+GalN model reproduced hallmark features of advanced ALD, including acute liver injury, sustained inflammation, induction of pro-fibrotic gene markers, reduced hepatic synthetic function, and markedly impaired regenerative capacity. RvD1 treatment significantly mitigated EtOH+GalN-induced pathology, lowering plasma endotoxin and ALT levels, reducing hepatic necrosis, and limiting neutrophil infiltration. RvD1 also decreased hepatic IL-6 levels at 9 hours and reduced IFN-γ at 48 hours. In addition, RvD1 attenuated the expression of pro-fibrotic genes and improved the diminished regenerative response in EtOH+GalN-treated mice, increasing hepatocyte proliferation at 48 hours and partially restoring plasma albumin concentrations.
CONCLUSION: This study established an EtOH+GalN exposure mouse model of severe ALD and demonstrated that RvD1 exerts significant hepatoprotective effects. The findings support RvD1 as a promising therapeutic candidate for advanced ALD and provide the rationale for further mechanistic studies and translational evaluation.
PMID:42678242 | DOI:10.1097/HC9.0000000000001039
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