Therapeutic Activity of Resolvin D1 (RvD1) in Murine MASH

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.

Impact and implications

Metabolic dysfunction–associated steatohepatitis (MASH) is an increasing healthcare burden worldwide. Current treatments for MASH and its sequelae are very limited. Recent studies highlighted the therapeutic benefit of specialized pro-resolving mediators (SPMs), including resolvin D1 (RvD1), in liver diseases. However, the mechanisms underlying these beneficial effects are not well understood. Based on unbiased transcriptomic analyses using bulk and single-cell RNA sequencing in RvD1-treated MASH livers, we show that RvD1 suppresses Stat1-mediated inflammatory responses and ER stress-induced apoptosis, and induces gene expression related to fibrosis regression. Our study provides new mechanistic insight into the role of RvD1 in MASH and highlights its therapeutic potential to treat MASH.

Highlights

• Liver RvD1 levels are decreased in MASH patients and MASH mice

• RvD1 administration suppresses Stat1-mediated inflammatory response

• RvD1 administration alleviates ER stress-induced apoptosis

• RvD1 administration induces fibrosis regression gene expression