Resolvin D1-mediated cellular crosstalk protects against MASH
Background & aims: Recent studies have highlighted the beneficial effect of resolvin D1 (RvD1), a docosahexaenoic acid-derived specialized pro-resolving mediator, on chronic liver diseases, but the underlying mechanisms are not well understood. Our study aimed to determine the role and mecha...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-08-01
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| Series: | JHEP Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555925001326 |
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| Summary: | Background & aims: Recent studies have highlighted the beneficial effect of resolvin D1 (RvD1), a docosahexaenoic acid-derived specialized pro-resolving mediator, on chronic liver diseases, but the underlying mechanisms are not well understood. Our study aimed to determine the role and mechanism of RvD1-mediated cellular crosstalk in metabolic dysfunction-associated steatohepatitis (MASH). Methods: RvD1 was administered to mice with experimental MASH, followed by bulk and single cell RNA sequencing (scRNA-seq) analysis. Primary liver cells, including primary hepatocytes, Kupffer cells (KCs), T cells, and hepatic stellate cells (HSCs), were isolated for co-culture experiments to elucidate the effect of RvD1 on cell death, inflammation, and fibrosis. Results: Hepatic tissue levels of RvD1 were decreased in murine (n = 5–6, p <0.01) and human MASH (n = 9–10, p <0.05). Administering RvD1 reduced hepatocellular death, inflammation, and liver fibrosis in MASH (n = 4–5, p <0.05). Mechanistically, RvD1 reduced hepatocyte death by suppressing endoplasmic reticulum (ER) stress. Co-culture experiments with primary liver cells showed that conditioned media from palmitic acid-treated hepatocytes activated KCs, T cells, and HSCs; however, those effects were abolished from RvD1-pretreated hepatocytes. Moreover, RvD1 directly suppressed T cell activation and IFNγ production, leading to reduced Stat1-Cxcl10 signaling in KCs. Conclusions: RvD1 reduced hepatocyte death and DAMP production by alleviating ER stress-mediated apoptosis, leading to decreased activation of KCs, T cells, and HSCs. This study highlights the novel role of RvD1-mediated cellular crosstalk among different liver cells in MASH. Impact and implications: MASH is a growing healthcare burden worldwide. However, current treatments for MASH and its sequelae remain limited. Recent studies highlighted the therapeutic benefit of specialized pro-resolving mediators (SPMs), including RvD1, in liver diseases. However, the mechanisms underlying these beneficial effects are not well understood. Based on a series of co-culture primary cell experiments and unbiased transcriptomic analyses, we show that RvD1-mediated cellular crosstalk among hepatocytes and nonparenchymal cells protects against MASH progression. Our study provides a new mechanistic insight into the role of RvD1 in MASH and highlights its therapeutic potential to treat this condition. |
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| ISSN: | 2589-5559 |