ABSTRACT
Background and Aims: Recent studies have highlighted the beneficial effect of resolvin D1 (RvD1), a DHA-derived specialized pro-resolving mediator, on metabolic dysfunction-associated steatohepatitis (MASH), but the underlying mechanisms are not well understood. Our study aims to determine the mechanism by which RvD1 protects against MASH progression. Methods: RvD1 was administered to mice with experimental MASH, followed by bulk and single-cell RNA sequencing analysis. Primary cells including bone marrow-derived macrophages (BMDMs), Kupffer cells, T cells, and primary hepatocytes were isolated to elucidate the effect of RvD1 on inflammation, cell death, and fibrosis regression genes. Results: Hepatic tissue levels of RvD1 were decreased in murine and human MASH, likely due to an expansion of pro-inflammatory M1-like macrophages with diminished ability to produce RvD1. Administering RvD1 reduced inflammation, cell death, and liver fibrosis. Mechanistically, RvD1 reduced inflammation by suppressing the Stat1-Cxcl10 signaling pathway in macrophages and prevented hepatocyte death by alleviating ER stress-mediated apoptosis. Moreover, RvD1 induced Mmp2 and decreased Acta2 expression in hepatic stellate cells (HSCs), and promoted Mmp9 and Mmp12 expression in macrophages, leading to fibrosis regression in MASH. Conclusions: RvD1 reduces Stat1-mediated inflammation, mitigates ER stress-induced apoptosis, and promotes MMP-mediated fibrosis regression in MASH. This study highlights the therapeutic potential of RvD1 to treat MASH.
