Resolvin D1-mediated cellular crosstalk protects against MASH

Amaia Navarro-Corcuera; Yiwei Zhu; Fanglin Ma; Neha Gupta; Haley Asplund; Bruno Cogliati; Jerry E Chipuk; Oren Rom; Scott L Friedman; Brian E Sansbury; Xin Huang; Bishuang Cai

doi:10.1016/j.jhepr.2025.101454

. 2025 May 14;7(8):101454. doi: 10.1016/j.jhepr.2025.101454

Resolvin D1-mediated cellular crosstalk protects against MASH

Amaia Navarro-Corcuera ^1,^†, Yiwei Zhu ^1,^†, Fanglin Ma ¹, Neha Gupta ¹, Haley Asplund ², Bruno Cogliati ¹, Jerry E Chipuk ³, Oren Rom ⁴, Scott L Friedman ¹, Brian E Sansbury ², Xin Huang ^5,^⁎, Bishuang Cai ^1,^6,^7,^⁎

PMCID: PMC12260426 PMID: 40671835

Abstract

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.

Keywords: SPMs, RvD1, MASH

Graphical abstract

Highlights

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Liver RvD1 levels are decreased in patients and mice with MASH.
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RvD1 alleviates ER stress-induced hepatocyte apoptosis.
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RvD1 mitigates inflammation and fibrosis by mediating cellular crosstalk between hepatocytes and nonparenchymal cells.
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RvD1 suppresses Stat1 signaling by mediating cellular crosstalk between T cells and KC.

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading forms of chronic liver disease, estimated to affect a quarter of the world’s population.¹^,² Of those with MASLD, 20–30% will develop metabolic dysfunction-associated steatohepatitis (MASH), a condition characterized by chronic inflammation, hepatocellular damage, and fibrosis.¹ Without treatment, MASH can further progress to cirrhosis and hepatocellular carcinoma. However, current treatments for MASH and its sequelae are very limited. This is largely due to our lack of understanding of MASH progression, particularly from steatosis to liver fibrosis, the main determinant of long-term mortality in MASH.³ Although the FDA has approved resmetirom, a thyroid hormone receptor β-selective agonist, as the first drug to treat MASH with fibrosis, only ∼25% of patients benefit from this treatment.⁴ Therefore, exploring new therapeutic strategies is essential.

Cell death and inflammation, two highly interconnected processes, are hallmarks of MASH, and are widely recognized as drivers of MASH progression.⁵ Fat overload induces lipotoxicity-mediated apoptosis in hepatocytes, leading to the release of damage-associated molecular patterns (DAMPs), which then activate resident immune cells, including resident Kupffer cells (KCs), to produce inflammatory cytokines and chemokines, promoting further immune cell infiltration into the liver.⁶ As MASLD progresses, monocytes are rapidly recruited to the liver, where they can differentiate into macrophages.¹^,⁶ By interacting with other liver cells, macrophages reshape the hepatic immune cell landscape during MASH, with direct consequences for disease severity. An excess of cytokines that results from uncontrolled inflammation can amplify hepatocyte apoptosis.⁶ This positive feedback loop of apoptosis–inflammation leads to the activation of hepatic stellate cells (HSCs), the major collagen-producing cells in the liver, and to fibrosis progression in MASH.⁷ Agents targeting inflammation and cell death, such as the chemokine antagonist, cenicriviroc, and the caspase inhibitor, emricasan, have been tested in clinical trials of MASH, but their efficacy in reducing MASH has been limited.⁸^,⁹ Thus, new therapeutic approaches that effectively resolve uncontrolled inflammation and cell death are needed.

Recent research has focused on the role of inflammation resolution in chronic inflammatory diseases.¹⁰ Inflammation resolution is mediated, in part, by a class of lipid-derived autacoids called specialized pro-resolving mediators (SPMs), generated from the enzymatic metabolism of polyunsaturated fatty acids by lipoxygenases (LOX) in myeloid cells, including macrophages.¹⁰ SPMs act as stop signals in the inflammatory response to facilitate the timely resolution of inflammation, while simultaneously stimulating tissue repair by blocking further immune cell infiltration and promoting efferocytosis.¹⁰ However, in many chronic inflammatory diseases, SPM generation is impaired, which contributes to exacerbated tissue injury.⁵ Certain SPM analogs have been tested in clinical trials of infantile eczema, periodontal inflammation, and atherosclerotic cardiovascular disease, demonstrating a therapeutic potential.¹¹ Although the therapeutic efficacy of resolvin D1 (RvD1), a docosahexaenoic acid (DHA)-derived SPM, in reducing liver inflammation and fibrosis in chronic liver diseases has been demonstrated,¹² the mechanisms underlying its beneficial effects in liver injury have not yet been fully characterized. RvD1 elicits its pro-resolving effects via its activation of the G-protein-coupled receptors, FPR2 and GPR32.¹³ RvD1 signaling through FPR2 has been shown to be essential for recovery from ischemic vascular injury.¹³ However, how RvD1 and its receptors are regulated in MASH remains unknown.

In this study, we demonstrate that liver levels of RvD1 and FPR2 are decreased in patients with MASH and in MASH mice. Using bulk- and single cell RNA sequencing (scRNA-seq), we further elucidate novel mechanisms by which RvD1 alleviates cell death, inflammation, and fibrosis in MASH. Specifically, we uncover that RvD1 suppresses hepatocyte death and DAMP production by mitigating endoplasmic reticulum (ER) stress-induced apoptosis. Co-culture experiments with primary liver cells indicate that RvD1 reverses the detrimental effect of injured hepatocytes on nonparenchymal cells (NPCs). In particular, RvD1-treated hepatocytes attenuate the activation of KCs, T cells, and HSCs, leading to reduced inflammation and fibrosis. Given that the beneficial effects of SPM analogs have been overlooked in MASH, our novel mechanistic study highlights their therapeutic potential (i.e. RvD1) in addressing MASH.

Materials and methods

Animal model

Male wild type (WT) C57BL/6J mice (Jackson Laboratory, #000664, Bar Harbor, ME, USA), aged 7–10 weeks, were used in the study. The mice were fed several MASH diets, as previously described:[14], [15], [16] Fibrosis and Tumors (FAT)-MASH diet (Teklad Diets, TD.120528, West Lafayette, IN, USA); fructose, palmitate, cholesterol, and trans-fat diet (FPC, Teklad Diets, TD.160785 PWD); high-fat, choline-deficient, L-amino-defined diet (CDAHFD, Research Diet, A06071302, New Brunswick, NJ, USA); and high-fat, high-fructose, and high-cholesterol diet (FFC also called AMLN, Research Diet, D17010103). For the RvD1 administration experiment, the mice were fed a FAT-MASH diet, containing 21.1% fat, 41% sucrose, and 1.25% cholesterol by weight, and a high-sugar solution (23.1 g/L d-fructose and 18.9 g/L d-glucose) for a total of 12 weeks. Simultaneously, the mice received intraperitoneal CCl₄ (0.32 μg/g body weight) once a week. At the 7-week time point, the mice were also intraperitoneally injected with 200 μl sterile PBS (vehicle) or RvD1 (500 ng/mouse, Cayman Chemical, #10012554, Ann Arbor, MI, USA) three times per week for 5 additional weeks while still on the FAT-MASH diet. The animals received humane care and were maintained on a 12 h light/dark cycle. All animal experiments were approved by the Animal Care and Use Committee of Icahn School of Medicine at Mount Sinai (New York, NY, USA).

Human liver specimens

Deidentified human liver specimens were acquired from the Liver Tissue Cell Distribution System at the University of Minnesota (Minneapolis, MN, USA), and all participants provided written informed consent. The diagnostic information is included in Table S1. All human studies and analyses were performed under Icahn School of Medicine at Mount Sinai institutional review board-approved protocols.

Study protocol

Please see the supplemental materials and methods for details of the study protocol.

Results

RvD1-FPR2 signaling is impaired in human and mouse MASH livers

RvD1 is metabolized by 15-LOX from DHA (Fig. 1A, left). To determine whether RvD1 is dysregulated in human MASH, we performed targeted liquid chromatography (LC)-mass spectrometry (MS)/MS to detect endogenous RvD1 levels in human livers. Strikingly, we found that liver RvD1 levels were dramatically decreased in patients with MASH (Fig. 1A, right). Consistent with this, RvD1 was reduced in FAT-MASH mice (Fig. 1A, right). We then detected 17-HDHA, a 15-LOX-derived monohydroxy intermediate of RvD1, and found that its abundance was also decreased in both human and mouse MASH livers (Fig. 1B). These data indicate that RvD1 is dysregulated in MASH. We next sought to determine the underlying mechanisms. We found that the liver DHA content was decreased in MASH mice and in patients with MASH (Fig. S1A). Moreover, because MASH is associated with an increased ratio of proinflammatory M1-like macrophages to anti-inflammatory M2-like macrophages,¹⁷ we compared the ability of different macrophage populations to produce RvD1. As a proof of concept, M1 and M2 polarization was induced by treating bone marrow-derived macrophages (BMDMs) with LPS + IFNγ or IL-4, respectively, and was confirmed by the expression of iNOS and arginase 1 (Fig. S1B, left). M1-like macrophages produced less RvD1 compared with M2-like macrophages (Fig. S1B, right). Therefore, the decreased RvD1 in MASH livers could be attributed to decreased DHA and increased proinflammatory macrophages.

To examine whether the downstream signaling of RvD1 is affected in MASH, we determined the expression of FPR2, an RvD1 receptor, in several mouse models of MASH, including FAT-MASH, FPC-, CDAHFD-, and AMLN/FFC-induced MASH. Strikingly, liver FPR2 was significantly decreased in all the examined mouse MASH models (Fig. 1C). FRP2 was also reduced in primary hepatocytes isolated from FAT-MASH mice (Fig. S1C). Similar to mouse MASH livers, there was also reduced FPR2 in livers from patients with MASH (Fig. 1D). Moreover, immunofluorescence analysis based on co-staining for FPR2 and the hepatocyte marker hepatocyte-specific antigen (HAS) revealed that FPR2 was significantly reduced in hepatocytes of patients with MASH (Fig. 1E). Together, these data indicate that the RvD1-FPR2 signaling pathway is suppressed in human and murine MASH.

RvD1 administration mitigates MASH progression

We next treated MASH mice with RvD1 to determine whether increasing RvD1 bioavailability protects against MASH. We fed WT mice with the FAT-MASH diet for 7 weeks to establish early MASH, followed by a 5-week RvD1 treatment, with continuation of the model (Fig. 2A). As described in previous work with the FAT-MASH model,¹⁴ steatosis, inflammation, fibrosis, and plasma alanine aminotransferase (ALT) were significantly induced in FAT-MASH mice compared with chow-fed mice (Fig. 2B–D). Although the liver/body weight ratio, lipid droplet area, and plasma cholesterol levels were not statistically different between the FAT-MASH mice that were treated with RvD1 or with vehicle (Fig. S2A–C), RvD1 administration restored hepatic FPR2 levels and significantly reduced plasma ALT (Fig. 2D; Fig. S2D), consistent with a decrease in liver injury corresponding to reduced inflammation and fibrosis, as indicated by the reduced inflammatory cells and Sirius Red staining (Fig. 2B–C). The mRNA levels of proinflammatory mediators, including Tnf, Ccl2, Ifng, and Cxcl10, were also dramatically enhanced in FAT-MASH mice compared with chow mice, which was reversed by RvD1 treatment (Fig. 2E). Moreover, RvD1-treated FAT-MASH livers expressed less Acta2, an HSC activation marker (Fig. 2E), in line with the liver fibrosis-reducing effect of RvD1. To confirm the role of RvD1 in MASH using an additional model, we treated mice fed CDAHFD with RvD1 (Fig. S3A). Similar to FAT-MASH, RvD1 treatment did not alter the liver/body weight ratio or lipid droplet area in CDAHFD-induced MASH mice (Fig. S3B–C). However, RvD1 attenuated inflammation, as indicated by reduced inflammatory cells and inflammatory gene expression (Fig. S3C–D). Moreover, liver fibrosis trended downward upon RvD1 treatment (Fig. S3E). Notably, RvD1 treatment also lowered plasma ALT levels in mice fed CDAHFD (Fig. S3F), confirming its protective effects against liver injury, as found in the FAT-MASH model.

To further explore the beneficial effect of RvD1 on MASH, we performed bulk RNA-seq on liver RNA isolated from chow-fed mice, and vehicle- and RvD1-treated FAT-MASH mice (Fig. 2F, upper panel). Principal component analysis (PCA) of these RNA-seq samples revealed that the RvD1-treated MASH livers (Fig. 2F, green dots) were separated from the MASH livers (Fig. 2F, red dots) and, importantly, were closer to the chow/healthy livers (Fig. 2F, black dots) compared with MASH livers (Fig. 2F, bottom panel), indicating that RvD1 alleviates MASH.

Next, we compared differentially expressed genes (DEGs) between the different groups (Fig. 2G) and found that DEGs upregulated in the MASH group compared with the chow group were mostly (n = 274) downregulated in MASH+RvD1 compared with the MASH group (Fig. 2H). Similarly, DEGs downregulated in the MASH group compared with the chow group were mostly (n = 100) upregulated in the MASH+RvD1 group compared with the MASH group (Fig. 2H). These results indicate that RvD1 treatment inhibits MASH progression. Comparison by gene set enrichment analysis (GSEA) between the MASH+RvD1 and MASH groups revealed that the extrinsic apoptotic signaling pathway, response to ER stress, and myeloid leukocyte activation were downregulated in RvD1-treated MASH livers (Fig. 2I). Together, these results indicate that RvD1 protects against MASH.

RvD1 reduces cell death by suppressing the ROS-CHOP pathway in hepatocytes

RNA-seq of RvD1-treated MASH livers demonstrated that RvD1 suppresses pathways underlying ER stress and cell death (Fig. 2I). Therefore, we explored the role of RvD1 in cell death in MASH. RvD1 suppressed the expression of cell death-related genes in MASH livers (Fig. 3A). Levels of cleaved caspase-3 and TUNEL, markers of cell death in MASH livers, were attenuated in RvD1-treated MASH livers (Fig. 3B,C). Given that hepatocyte apoptosis strongly correlates with MASH progression,¹⁸ we next determined whether RvD1 prevents apoptosis in primary hepatocytes. Although palmitic acid (PA), a saturated fatty acid, does not completely reflect the lipid environment in MASH, it has been commonly used to elicit lipotoxicity and cell death in hepatocytes.¹⁹ Thus, we treated primary hepatocytes with PA in the presence or absence of RvD1. As expected, PA-induced apoptosis, as indicated by increased cleaved caspase-3; however, RvD1 prevented PA-induced apoptosis in primary hepatocytes (Fig. 3D). To determine whether the effect of RvD1 on cell death is specific to PA-mediated lipotoxicity, primary hepatocytes were exposed to TNFα/Jo2 to induce death receptor-mediated apoptosis.²⁰ Interestingly, RvD1 also suppressed death receptor-induced cell death (Fig. S4A). Dead hepatocytes can be surrounded by aggregated macrophages that form crown-like structures in MASH.²¹ Consistent with this concept, RvD1 reduced the number of crown-like structures in FAT-MASH livers (Fig. S4B).

Fig. 3 — RvD1 inhibits ROS production, ER stress, and apoptosis.

(A) Heatmap depicting the expression of cell death-related genes. (B) Immunoblot of cleaved caspase-3 in MASH livers. (C) TUNEL staining in MASH livers. The number of TUNEL⁺ cells was quantified by ImageJ. (D) Immunoblot of cleaved caspase-3 in primary hepatocytes treated with BSA or 100 μM PA ± 50 nM RvD1 for 24 h. (E) Co-immunostaining showing ROS levels in HNF4a⁺ cells in MASH livers. White arrows indicate the co-staining of ROS and HNF4a. (F) ROS staining in primary hepatocytes treated with BSA or PA ± RvD1. (G) qRT-PCR and immunoblot of CHOP in primary hepatocytes treated with BSA or PA ± RvD1. (H) Measurement of released HMGB1 in supernatants from primary hepatocytes treated with 100 μM PA or BSA ± 100 nM RvD1 for 48 h In (E, F), ROS MFI was quantified by ImageJ. Data are presented as mean ± SD; in (C, D) n = 5 mice/group; unpaired Student t test: ∗p <0.05, ∗∗p <0.01 compared with MASH group; in (E), n = 4 and (G, H) n = 3; one-way ANOVA with Dunnett comparison ∗∗p <0.01, ∗∗∗p <0.001. Scale bars: 50 μm. CHOP, C/EBP homologous protein; ER, endoplasmic reticulum; HMGB1, high-mobility group box 1; MASH, metabolic dysfunction-associated steatohepatitis; MFI, mean fluorescence intensity; PA, palmitic acid; ROS, reactive oxygen species; RvD1, resolvin D1; UT, untreated.

We next sought to determine the mechanism by which RvD1 suppresses cell death. Given that RvD1 has been shown to reduce reactive oxygen species (ROS) production²² and that ROS can promote ER stress-induced apoptosis,²³ we assessed ROS levels in HNF4α ⁺ hepatocytes from MASH livers and found that ROS was significantly decreased in hepatocytes of RvD1-treated FAT-MASH livers (Fig. 3E). Consistent with these in vivo findings, RvD1 inhibited PA-induced ROS production in primary hepatocytes (Fig. 3F). To link RvD1-reduced ROS to ER stress, we examined whether RvD1 regulates PA-induced ER stress in primary hepatocytes and found that PA induced the expression of C/EBP homologous protein (CHOP, encoded by Ddit3), an ER stress marker; however, RvD1 blocked this induction (Fig. 3G). Given that optimal mitochondrial respiration can reduce ROS production and ER stress,²⁴^,²⁵ and RvD1 promotes mitochondrial respiration in macrophages,²⁶^,²⁷ we measured the mitochondrial respiration rate in PA-treated hepatocytes by seahorse assay, which demonstrated that RvD1 enhanced the oxygen consumption rate (OCR) (Fig. S4C), suggesting that RvD1-reduced ROS occurs by promoting mitochondrial respiration. Moreover, consistent with reduced hepatocyte death, RvD1 suppressed the release of high-mobility group box 1 (HMGB1) from injured hepatocytes (Fig. 3H), a well-characterized DAMP that contributes to the pathogenesis of MASH.²⁸ These data suggest that RvD1 suppresses hepatocyte death and DAMP production by alleviating ROS/CHOP-mediated apoptosis during lipotoxicity.

scRNA-seq reveals the protective effect of RvD1 against immune cell activation

To explore the regulation of RvD1 in immune cell populations, we performed scRNA-seq in NPCs isolated from MASH livers. A total of 28,059 single cell transcriptomes were analyzed. Clustering visualized on uniform manifold approximation and projection (UMAP) revealed 10 major clusters of cells (Fig. 4A; Fig. S5A), including endothelial cells, dendritic cells, macrophages, HSCs, T cells, B cells, hepatocytes, and cholangiocytes, and was annotated with lineage-specific marker genes (Fig. 4B).

Fig. 4 — Single cell RNA-seq analysis reveals that RvD1 suppresses macrophage activation in MASH liver.

(A) UMAP visualization of liver cells based on 28,059 single cell transcriptomes (cell counts are in parentheses). (B) Violin plots of representative marker gene expression for each cell type. (C) Volcano plot of macrophage DEGs by comparing MASH+RvD1 *vs.* MASH groups. (D) Gene ontology (GO) analysis for the downregulated and upregulated DEGs in macrophages. (E,F) UMAP plots for (E) all macrophages and (F) macrophage subclusters in chow, MASH, and MASH + RvD1 groups. (G) Percentage cell counts in each macrophage subcluster. (H) GO analysis for downregulated and upregulated DEGs in c-LAMs, LAMs-1, and LAMs-2 macrophage subclusters by comparing MASH + RvD1 *vs.* MASH groups. (I) Dot plots of *Tnf*, *Ccl2*, *Cxcl10,* and *Ifng* expression in macrophages and T cells (n = 2 mice/group). C-LAMs, Cx3cr1+Ccr2+ transitional lipid-associated macrophages; DEG, differentially expressed gene; GO, Gene Ontology; LAMs-1, Trem2^highCd63^highGpnmb^highSpp1^low lipid-associated macrophages; LAMs-2, Trem2^lowCd63^lowGpnmb^lowSpp1^high lipid-associated macrophages; MASH, metabolic dysfunction-associated steatohepatitis; RNA-seq, RNA sequencing; RvD1, resolvin D1; UMAP, uniform manifold approximation and projection.

Given that macrophages are the most prominent immune cells in MASH livers,²⁹ we determined the effect of RvD1 on this cell population. We performed DEG analysis in macrophages and identified 631 downregulated and 1,136 upregulated genes by comparing MASH+RvD1 with MASH (Fig. 4C). Gene ontology (GO) analysis for these DEGs demonstrated that biological processes, including immune system process, response to ER stress, IFNγ-mediated signaling pathway, and TNF production, were significantly enriched in downregulated DEGs (Fig. 4D, left). By contrast, mitochondrial ATP synthesis, aerobic respiration, fatty acid β-oxidation, and cholesterol efflux were significantly enriched in upregulated DEGs (Fig. 4D, right). Macrophages are highly heterogeneous in MASH livers; therefore, by comparing marker genes as described previously,[30], [31], [32] we subclustered macrophages into five major populations: Timd4^high Macro^high resident KCs; Timd4^low Macro^low Vsig4⁺Clec4f⁺ monocyte-derived KCs (mo-KCs); Trem2^highCd63^highGpnmb^highSpp1^low lipid-associated macrophages (LAMs-1); Trem2^lowCd63^lowGpnmb^lowSpp1^high lipid-associated macrophages (LAMs-2); and Cx3cr1⁺Ccr2⁺ transitional lipid-associated macrophages (c-LAMs) (Fig. 4E; Fig. S5B). As predicted, chow mice predominantly harbored resident KCs, whereas both MASH and RvD1-treated MASH mice had infiltrated mo-KCs, LAMs-1, LAMs-2, and c-LAMs (Figs. 4F). Although the compositions of F4/80⁺TIM4⁺ KCs and F4/80⁺Mac2⁺ LAMs were not affected by RvD1 treatment (Fig. 4G; Fig. S5C and D), c-LAMs localizing to macrophage aggregates in the crown-like structures³² were decreased in RvD1-treated MASH mice compared with non-treated MASH mice (Fig. 4G). Interestingly, the LAMs-2 population was increased in RvD1-treated MASH mice (Fig. 4G). GO analysis of the DEGs in LAMs revealed downregulation of the immune system process, cellular response to interferon, and apoptotic process, whereas mitochondrial function and cholesterol efflux were upregulated in RvD1-treated MASH livers (Fig. 4H). Of note, the collagen catabolic process pathway was upregulated in LAMs-2, indicating that this LAM population may protect against fibrosis (Fig. 4H, arrow labeled). The enriched genes involved in the collagen catabolic process pathway included Adam15, Ctsl, Mmp12, and Mmp14 (Fig. S5E). Intriguingly, the LAMs-2 population also highly expressed osteopontin (OPN, Spp1) and RvD1 treatment enhanced OPN⁺ macrophages (Fig. S5B and F), which was recently shown to protect against MASH progression.³³ Spp1^high macrophages express higher levels of genes that regulate extracellular matrix remodeling, such as MMPs,³³ indicating the potential role of Spp1 in facilitating the resolution of liver fibrosis. Similar to the effect in macrophages, RvD1 treatment downregulated pathways involved in TNF production, antigen processing and presentation, and apoptosis, while upregulating pathways involved in mitochondrial ATP synthesis and aerobic respiration in dendritic cells, a myeloid lineage closely related to macrophages (Fig. S5G–H). Finally, consistent with the decreased proinflammatory gene expression in RvD1-treated MASH livers (Fig. 2E), Tnf, Ccl2, and Cxcl10 expression in liver macrophages and Ifng expression in T cells was lower in RvD1-treated MASH mice (Fig. 4I). These results confirm that RvD1 alleviates inflammation by suppressing the activation of immune cells in MASH.

RvD1-mediated cellular crosstalk among hepatocytes, KCs, and T cells alleviates inflammation

Our RNA-seq data showed that RvD1 treatment downregulated proinflammatory genes, including Cxcl10, Ccl2, Tnf, and Ifng, in MASH livers (Fig. 5A). We first examined whether RvD1 directly suppresses the activation of isolated KCs. Surprisingly, RvD1 did not reduce Cxcl10, Ccl2, and Tnf expression in either resting or LPS-activated KCs (Fig. S6A). Given that dying hepatocytes can activate immune cells through released DAMPs,³⁴ we performed a hepatocyte–KC co-culture experiment by treating KCs with conditioned media collected from PA-induced injured primary hepatocytes that had been pretreated without or with RvD1 (Fig. 5B). Interestingly, conditioned media from PA-treated hepatocytes induced Tnf, Ccl2, Cxcl10, Il1b, Nos2, and Il6 expression in KCs, but RvD1 pretreatment suppressed this induction (Fig. 5B; Fig. S6B). Similarly, hepatocyte and T cell co-culture experiments showed that conditioned media from PA-treated hepatocytes induced IFNγ expression in T cells and that RvD1 pretreatment abolished this induction (Fig. 5C). These data suggest that RvD1 mitigates the detrimental effect of injured hepatocytes on KC and T cell activation, leading to decreased inflammation.

Given that SPMs, including RvD1, have been shown to reduce IFNγ production in human circulating T cells,³⁵ we next investigated whether RvD1 directly suppresses IFNγ production in liver T cells. We activated isolated liver T cells with anti-CD3/CD28 antibodies³⁶ to induce IFNγ production in the absence or presence of RvD1. As expected, RvD1 suppressed IFNγ production in liver T cells (Fig. 5D). Given that IFNγ, by activating the transcription factor Stat1,³⁷ can induce Cxcl10, which is highly expressed in liver mononuclear phagocytes (Fig. S6C), we sought to determine whether RvD1-treated T cells modulate KC activation. Conditioned media from activated T cells induced Cxcl10 as well as Tnf, Ccl2, Il1b, and Il6 expression in KCs, whereas RvD1 pretreatment reduced the effect of activated T cells on KC activation (Fig. 5E; Fig. S6D). Accordingly, Stat1 activation, as determined by phosphorylated Stat1 (p-Stat1), was decreased in RvD1-treated MASH livers and in Mac2⁺ MASH macrophages, as well as in KCs that had been co-cultured with RvD1-treated T cells (Fig. 5F–H). We next determined the direct effect of IFNγ on macrophages and found that it activated Stat1 and induced Cxcl10 in KCs as well as BMDMs (Fig. 5I–J). These data indicate that RvD1 modulates the cellular crosstalk between T cells and macrophages to suppress IFNγ/Cxcl10-mediated inflammation.

RvD1 suppresses HSC activation and liver fibrosis in MASH

We next explored the mechanism by which RvD1 reduces liver fibrosis in MASH. We performed DEG analysis in the HSC population revealed by scRNA-seq and identified 356 downregulated and 748 upregulated genes by comparing RvD1-treated MASH with MASH (Fig. 6A). GO analysis of these DEGs revealed that cell migration and proliferation were downregulated, whereas aerobic respiration and mitochondrial ATP synthesis were upregulated in HSCs from RvD1-treated MASH livers (Fig. 6B). We further found that RvD1 treatment decreased Acta2, Col1a1, Col1a2, Col3a1, and Col4a1 expression in HSCs in MASH livers (Fig. 6C). Consistent with this, RvD1 suppressed HSC activation, as indicated by reduced αSMA staining (Fig. 6D). To determine whether RvD1 has a direct role in suppressing HSC activation, we treated primary HSCs with RvD1. However, RvD1 did not reduce Acta2, collagen genes, or Tgfb1 expression (Fig. S7A). Given that dying hepatocytes promote fibrogenesis via releasing DAMPs in chronic liver disease,³⁴ we explored whether RvD1 suppresses liver fibrosis through mitigating the detrimental effect of damaged hepatocytes on HSC activation. Our hepatocyte and HSC co-culture experiment revealed that conditioned media from PA-treated hepatocytes induced Acta2, Col1a1, Col1a2, Col3a1, and Col4a1 expression in HSCs, but hepatocytes with RvD1 pretreatment did not (Fig. 6E). Collagens can be degraded by MMPs and other matrix-degrading enzymes, leading to fibrosis regression.³⁸ Macrophages are an important source of collagen-degrading enzymes³⁹^,⁴⁰; thus, determined whether RvD1 regulates collagen-degrading enzymes in macrophages. scRNA-seq of MASH livers demonstrated that RvD1 treatment enhanced Mmp12, Mmp14, Adam15, and Ctsl expression in macrophages (Fig. 6F). Interestingly, Mmp12 was specifically expressed in macrophages (Fig. S7B) and RvD1 enhanced Mmp12 expression in LPS-activated KCs and BMDMs (Fig. 6G). Consistent with a recent study showing that the prominent HSC autocrine signaling circuit is a key driver of MASH fibrosis,⁴¹ our CellphoneDB analysis successfully captured increased HSC–HSC interactions in FAT-MASH mice compared with chow mice and also demonstrated that RvD1 attenuated HSC–HSC interactions in MASH (Fig. 6H). Specifically, the interactions of PDGF, FGF, and Ephrin with their receptors decreased in HSCs from RvD1-treated mice (Fig. S7C). Although a mild decrease in macrophage–HSC interaction upon RvD1 treatment was observed (Fig. 6H), several TNF and TNF receptor-mediated interactions were decreased (Fig. S7D). These ligand–receptor signaling pathways can reduce fibrosis.[42], [43], [44], [45] Together, our data suggest that RvD1 protects against liver fibrosis by alleviating the detrimental effect of injured hepatocytes on HSC activation, enhancing collagen-degrading enzyme expression in macrophages, and eliminating HSC autocrine signaling and macrophage–HSC interactions.

Fig. 6 — Protective role of RvD1 in HSC activation and liver fibrosis.

(A) Volcano plot of DEGs in HSCs by comparing MASH+RvD1 *vs.* MASH groups. (B) GO analysis for downregulated and upregulated DEGs in HSCs. (C) Dot plot of selected genes in HSCs. (D) αSMA immunostaining in mouse MASH livers. (E) Schematic for experiment and qRT-PCR of mRNA levels of *Acta2* and collagens in primary HSCs incubated with conditioned media from primary hepatocytes treated with 100 μM PA or BSA ± 100 nM RvD1. (F) Dot plot of selected genes in macrophages. (G) KCs or BMDMs were activated with 50 ng/ml LPS ± 50 nM RvD1 for 18 h *Mmp12* mRNA levels were detected by qRT-PCR. (H) Cell–cell interaction heatmap between different cell types from CellphoneDB analysis. The asterisk indicates the self-interaction of HSCs. Color scale of interaction counts is provided. Data are presented as mean ± SD; in (A–C, H) n = 2 mice/group; in (C) n = 4–5 mice/group; in (E, G) n = 3 mice/group; one-way ANOVA with Dunnett comparison: ∗p <0.05, ∗∗p <0.01, ∗∗∗p <0.001, ∗∗∗∗p <0.0001. Scale bar: 100 μm. BMDM, bone marrow-derived macrophage; DEG, differentially expressed gene; GO, Gene Ontology; HSC, hepatic stellate cell; KC, Kupffer cell; MASH, metabolic dysfunction-associated steatohepatitis; RvD1, resolvin D1.

Discussion

Using LC-MS/MS, we elucidated that RvD1 levels are decreased in human MASH livers, while scRNA-seq in RvD1-treated mouse MASH livers confirmed the beneficial effects of RvD1 on MASH. Mechanistically, we demonstrated that RvD1 alleviates cell death by suppressing ER stress and DAMP production. We also identified novel roles of RvD1-mediated cellular crosstalk among hepatocytes, KCs, T cells, and HSCs in mitigating MASH progression. Our co-culture experiments with primary liver cells suggest that RvD1 mitigates the detrimental effects of injured hepatocytes on KCs, T cells, and HSCs, leading to reduced inflammation and fibrosis in MASH.

Our study suggests that reduced RvD1 results from decreased DHA and increased proinflammatory macrophages in MASH livers. Given that DHA deficiency can be associated with a proinflammatory phenotype in macrophages,⁴⁶ future studies will need to investigate whether DHA synthetic pathways and RvD1 biosynthetic enzyme activity or expression differ across macrophage subsets in MASH. In addition to reduced RvD1, we found that FPR2, one of the well-characterized RvD1 receptors, is decreased in MASH livers, suggesting that RvD1–FPR2 signaling is suppressed in MASH. However, we did not observe a decrease in Fpr2 mRNA in MASH livers (data not shown). Therefore, FPR2 might be regulated at a post-transcriptional level in response to MASH. FPR2 is expressed in hepatocytes,⁴⁷ myeloid cells,⁴⁸ and T cells,³⁵ and binds a range of ligands that trigger either a proinflammatory or an anti-inflammatory response.⁴⁸^,⁴⁹ For instance, polypeptides, including serum amyloid A (SAA) and β-amyloid peptide 42 (Aβ₄₂), elicit the proinflammatory effect of FPR2, whereas bioactive lipid molecules, such as annexin A1, lipoxin A4, and RvD1, trigger anti-inflammatory signaling of FPR2.⁴⁸^,⁴⁹ Given the complexity of FPR2 biology, the roles of FPR2 signaling in different liver cell types in the context of MASH warrant future investigation.

Hepatocyte apoptosis is an important feature of MASH and one of the primary causes of liver inflammation and fibrosis.¹⁸ We showed that RvD1 prevents both PA- and Fas (Jo2)-induced apoptosis, likely by suppressing ER stress in primary hepatocytes. Notably, DEG analysis from scRNA-seq revealed that RvD1 also suppresses the apoptotic process in immune cells, indicating that RvD1 has a broad anti-apoptotic activity in MASH. Our transcriptomic studies demonstrated that RvD1 suppresses the activation of immune cells and HSCs in MASH livers. However, to our surprise, RvD1 had no direct role in regulating KC and HSC activation; instead, RvD1 indirectly suppressed KC and HSC activation by alleviating the detrimental effects of injured hepatocytes. Hepatocyte-derived DAMPs, including HMGB1, DNA, and uric acid, can induce inflammation and fibrosis by stimulating pattern recognition receptors (PRRs) in NPCs.⁵⁰ Our study revealed that RvD1 reduces HMGB1 released from hepatocytes, potentially leading to decreased activation of immune cells and HSCs. Future studies are needed to elucidate specific DAMP-PRR signaling pathways mediated by RvD1 in MASH. Another new mechanism of RvD1-suppressed inflammation that we found is that RvD1 directly suppresses T cell activation and IFNγ production, leading to decreased Stat1-mediated proinflammatory signaling in macrophages. Finally, RvD1 may promote fibrosis regression by inducing collagen-degrading enzymes in macrophages, leading to an accelerated collagen catabolic process in MASH livers.

In conclusion, using unbiased transcriptomic approaches and a series of primary liver cell co-culture experiments, we established that RvD1 alleviates cell death, inflammation, and fibrosis by mediating cellular crosstalk. Our novel mechanistic study highlights the therapeutic potential of SPMs to boost tissue repair in MASH.

Abbreviations

Aβ₄₂, β-amyloid peptide 42; ALT, alanine aminotransferase; BMDM, bone marrow-derived macrophage; C-LAMs, Cx3cr1⁺Ccr2⁺ transitional lipid-associated macrophages; CDAHFD, high-fat, choline-deficient, L-amino-defined diet; CHOP, C/EBP homologous protein; DAMP, damage-associated molecular pattern; DHA, docosahexaenoic acid; DEG, differentially expressed gene; ER, endoplasmic reticulum; FAT, Fibrosis and Tumors; FDR, false discovery rate; FFC, high-fat, high-fructose, and high-cholesterol diet; FPC, fructose, palmitate, cholesterol, and trans-fat diet; GO, Gene Ontology; GSEA, gene set enrichment analysis; HSA, hepatocyte-specific antigen; HSC, hepatic stellate cell; HMGB1, high-mobility group box 1; HSC, hepatic stellate cell; KC, Kupffer cell;LAMs-1, Trem2^highCd63^highGpnmb^highSpp1^low lipid-associated macrophages; LAMs-2, Trem2^lowCd63^lowGpnmb^lowSpp1^high lipid-associated macrophages; LC, liquid chromatography; LOX, lipoxygenase; MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; MFI, mean fluorescence intensity; mo-KC, Timd4^low Macro^low Vsig4⁺Clec4f⁺ monocyte-derived Kupffer cell; MS, mass spectrometry; ND, not detected; NES, normalized enrichment score; NPC, nonparenchymal cell; OCR, oxygen consumption rate; OPN, osteopontin; p-Stat1, phosphorylated Stat1; PA, palmitic acid; PCA, principal component analysis; PRR, pattern recognition receptor; RNA-seq, RNA sequencing; ROS, reactive oxygen species; RvD1, resolvin D1; SAA, serum amyloid A; scRNA-seq, single cell RNA sequencing; SPM, specialized pro-resolving mediator; UMAP, uniform manifold approximation and projection; UT, untreated; WT, wild type.

Financial support

This work was supported, in part, by NIH grants R01DK134610, R01HL167107, and R35GM147269, the Irma T. Hirschl/Monique Weill-Caulier Trust Research Award (to B. Cai); R00HL150233, R01DK134011 and R01DK136685 (to OR); R21HD106263 and R35GM154906 (to XH); R01DK128289 (to SLF); and R01ES034389 (to BES.).

Authors’ contributions

Study concept and experimental design: B.Cai, XH. Bulk- and scRNA-sequencing data analysis: XH. Conducted animal study procedures and in vitro experiments: B.Cai, ANC, YZ, FM, NG, B.Cogliati. Helped establish the FAT-MASH mouse model and assisted with data analysis and writing: SLF. Performed targeted LC-MS/MS quantification of RvD1 and 17-HDHA: HA, BES. Helped with the seahorse assay: JEC. Provided lysates from FFC-induced MASH livers: OR. Interpreted the data and wrote the manuscript: B.Cai, ANC, XH. Manuscript editing and approved the final version: all authors.

Data availability statement

All data are available from the corresponding authors upon reasonable request. The RNA-seq data have been deposited in the Gene Expression Omnibus (GSE232780, GSE263768, and GSE263770).

Conflicts of interest

The authors declare no conflicts of interest that pertain to this work.

Please refer to the accompanying ICMJE disclosure forms for further details.

Acknowledgements

We thank the Liver Tissue Cell Distribution System at the University of Minnesota for providing human normal and MASH liver tissues. Parts of this work were previously posted as a preprint on bioRxiv at https://doi.org/10.1101/2024.04.22.590633.

Footnotes

Author names in bold designate shared co-first authorship

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jhepr.2025.101454.

Contributor Information

Xin Huang, Email: xh2200@cumc.columbia.edu.

Bishuang Cai, Email: bishuang.cai@mssm.edu.

Supplementary data

The following are the supplementary data to this article:

Multimedia component 1

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mmc2.pdf^{(144.2KB, pdf)}

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mmc3.pdf^{(1.3MB, pdf)}

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References

1.Loomba R., Friedman S.L., Shulman G.I. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell. 2021;184:2537–2564. doi: 10.1016/j.cell.2021.04.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Le P., Tatar M., Dasarathy S., et al. Estimated burden of metabolic dysfunction-associated steatotic liver disease in US adults, 2020 to 2050. JAMA Netw Open. 2025;8 doi: 10.1001/jamanetworkopen.2024.54707. [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Angulo P., Kleiner D.E., Dam-Larsen S., et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389–397. doi: 10.1053/j.gastro.2015.04.043. [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Harrison S.A., Bedossa P., Guy C.D., et al. A Phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497–509. doi: 10.1056/NEJMoa2309000. [DOI] [PubMed] [Google Scholar]
5.Schuster S., Cabrera D., Arrese M., et al. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol. 2018;15:349–364. doi: 10.1038/s41575-018-0009-6. [DOI] [PubMed] [Google Scholar]
6.Huby T., Gautier E.L. Immune cell-mediated features of non-alcoholic steatohepatitis. Nat Rev Immunol. 2022;22:429–443. doi: 10.1038/s41577-021-00639-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Tsuchida T., Friedman S.L. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14:397–411. doi: 10.1038/nrgastro.2017.38. [DOI] [PubMed] [Google Scholar]
8.Anstee Q.M., Neuschwander-Tetri B.A., Wai-Sun Wong V., et al. Cenicriviroc lacked efficacy to treat liver fibrosis in nonalcoholic steatohepatitis: AURORA Phase III randomized study. Clin Gastroenterol Hepatol. 2024;22:124–134. doi: 10.1016/j.cgh.2023.04.003. [DOI] [PubMed] [Google Scholar]
9.Harrison S.A., Goodman Z., Jabbar A., et al. A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. J Hepatol. 2020;72:816–827. doi: 10.1016/j.jhep.2019.11.024. [DOI] [PubMed] [Google Scholar]
10.Serhan C.N. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510:92–101. doi: 10.1038/nature13479. [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Serhan C.N., Levy B.D. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest. 2018;128:2657–2669. doi: 10.1172/JCI97943. [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Li J., Deng X., Bai T., et al. Resolvin D1 mitigates non-alcoholic steatohepatitis by suppressing the TLR4-MyD88-mediated NF-kappaB and MAPK pathways and activating the Nrf2 pathway in mice. Int Immunopharmacol. 2020;88 doi: 10.1016/j.intimp.2020.106961. [DOI] [PubMed] [Google Scholar]
13.Sansbury B.E., Li X., Wong B., et al. Myeloid ALX/FPR2 regulates vascularization following tissue injury. Proc Natl Acad Sci U S A. 2020;117:14354–14364. doi: 10.1073/pnas.1918163117. [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Tsuchida T., Lee Y.A., Fujiwara N., et al. A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. J Hepatol. 2018;69:385–395. doi: 10.1016/j.jhep.2018.03.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Shi H., Wang X., Li F., et al. CD47-SIRPalpha axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis. Sci Transl Med. 2022;14 doi: 10.1126/scitranslmed.abp8309. [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Rom O., Xu G., Guo Y., et al. Nitro-fatty acids protect against steatosis and fibrosis during development of nonalcoholic fatty liver disease in mice. EBioMedicine. 2019;41:62–72. doi: 10.1016/j.ebiom.2019.02.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Pant R., Kabeer S.W., Sharma S., et al. Pharmacological inhibition of DNMT1 restores macrophage autophagy and M2 polarization in Western diet-induced nonalcoholic fatty liver disease. J Biol Chem. 2023;299 doi: 10.1016/j.jbc.2023.104779. [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Lei Z., Yu J., Wu Y., et al. CD1d protects against hepatocyte apoptosis in non-alcoholic steatohepatitis. J Hepatol. 2024;80:194–208. doi: 10.1016/j.jhep.2023.10.025. [DOI] [PubMed] [Google Scholar]
19.Das S., Finney A.C., Anand S.K., et al. Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis. Nat Metab. 2024;6:1939–1962. doi: 10.1038/s42255-024-01134-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Hatano E. Tumor necrosis factor signaling in hepatocyte apoptosis. J Gastroenterol Hepatol. 2007;22(Suppl 1):S43–S44. doi: 10.1111/j.1440-1746.2006.04645.x. [DOI] [PubMed] [Google Scholar]
21.Ioannou G.N., Haigh W.G., Thorning D., et al. Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis. J Lipid Res. 2013;54:1326–1334. doi: 10.1194/jlr.M034876. [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Fredman G., Hellmann J., Proto J.D., et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun. 2016;7 doi: 10.1038/ncomms12859. [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Yang L., Zhou X., Sun J., et al. Reactive oxygen species mediate anlotinib-induced apoptosis via activation of endoplasmic reticulum stress in pancreatic cancer. Cell Death Dis. 2020;11:766. doi: 10.1038/s41419-020-02938-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Sung H.J., Ma W., Wang P.Y., et al. Mitochondrial respiration protects against oxygen-associated DNA damage. Nat Commun. 2010;1:5. doi: 10.1038/ncomms1003. [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Knupp J., Arvan P., Chang A. Increased mitochondrial respiration promotes survival from endoplasmic reticulum stress. Cell Death Differ. 2019;26:487–501. doi: 10.1038/s41418-018-0133-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Calderin E.P., Zheng J.J., Boyd N.L., et al. Exercise-induced specialized proresolving mediators stimulate AMPK phosphorylation to promote mitochondrial respiration in macrophages. Mol Metab. 2022;66 doi: 10.1016/j.molmet.2022.101637. [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Hosseini Z., Marinello M., Decker C., et al. Resolvin D1 enhances necroptotic cell clearance through promoting macrophage fatty acid oxidation and oxidative phosphorylation. Arterioscler Thromb Vasc Biol. 2021;41:1062–1075. doi: 10.1161/ATVBAHA.120.315758. [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Gaskell H., Ge X., Desert R., et al. Ablation of Hmgb1 in intestinal epithelial cells causes intestinal lipid accumulation and reduces NASH in mice. Hepatol Commun. 2020;4:92–108. doi: 10.1002/hep4.1448. [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Kazankov K., Jorgensen S.M.D., Thomsen K.L., et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2019;16:145–159. doi: 10.1038/s41575-018-0082-x. [DOI] [PubMed] [Google Scholar]
30.Remmerie A., Martens L., Thone T., et al. Osteopontin expression identifies a subset of recruited macrophages distinct from Kupffer cells in the fatty liver. Immunity. 2020;53:641–657. doi: 10.1016/j.immuni.2020.08.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Guilliams M., Bonnardel J., Haest B., et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell. 2022;185:379–396. doi: 10.1016/j.cell.2021.12.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Daemen S., Gainullina A., Kalugotla G., et al. Dynamic shifts in the composition of resident and recruited macrophages influence tissue remodeling in NASH. Cell Rep. 2021;34 doi: 10.1016/j.celrep.2020.108626. [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Han H., Ge X., Komakula S.S.B., et al. Macrophage-derived osteopontin (SPP1) protects from nonalcoholic steatohepatitis. Gastroenterology. 2023;165:201–217. doi: 10.1053/j.gastro.2023.03.228. [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Brenner C., Galluzzi L., Kepp O., et al. Decoding cell death signals in liver inflammation. J Hepatol. 2013;59:583–594. doi: 10.1016/j.jhep.2013.03.033. [DOI] [PubMed] [Google Scholar]
35.Chiurchiu V., Leuti A., Dalli J., et al. Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses. Sci Transl Med. 2016;8:353ra111. doi: 10.1126/scitranslmed.aaf7483. [DOI] [PMC free article] [PubMed] [Google Scholar]
36.Trickett A., Kwan Y.L. T cell stimulation and expansion using anti-CD3/CD28 beads. J Immunol Methods. 2003;275:251–255. doi: 10.1016/s0022-1759(03)00010-3. [DOI] [PubMed] [Google Scholar]
37.Shi D., Li Y., Shi X., et al. Transcriptional expression of CXCL10 and STAT1 in lupus nephritis and the intervention effect of triptolide. Clin Rheumatol. 2023;42:539–548. doi: 10.1007/s10067-022-06400-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Naim A., Pan Q., Baig M.S. Matrix metalloproteinases (MMPs) in liver diseases. J Clin Exp Hepatol. 2017;7:367–372. doi: 10.1016/j.jceh.2017.09.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
39.Fallowfield J.A., Mizuno M., Kendall T.J., et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol. 2007;178:5288–5295. doi: 10.4049/jimmunol.178.8.5288. [DOI] [PubMed] [Google Scholar]
40.Pellicoro A., Aucott R.L., Ramachandran P., et al. Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis. Hepatology. 2012;55:1965–1975. doi: 10.1002/hep.25567. [DOI] [PubMed] [Google Scholar]
41.Wang S., Li K., Pickholz E., et al. An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Sci Transl Med. 2023;15 doi: 10.1126/scitranslmed.add3949. [DOI] [PMC free article] [PubMed] [Google Scholar]
42.Ying H.Z., Chen Q., Zhang W.Y., et al. PDGF signaling pathway in hepatic fibrosis pathogenesis and therapeutics. Mol Med Rep. 2017;16:7879–7889. doi: 10.3892/mmr.2017.7641. [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Seitz T., Hellerbrand C. Role of fibroblast growth factor signalling in hepatic fibrosis. Liver Int. 2021;41:1201–1215. doi: 10.1111/liv.14863. [DOI] [PubMed] [Google Scholar]
44.Wijeratne D., Rodger J., Stevenson A., et al. Ephrin-A2 affects wound healing and scarring in a murine model of excisional injury. Burns. 2019;45:682–690. doi: 10.1016/j.burns.2018.10.002. [DOI] [PubMed] [Google Scholar]
45.Steele H., Cheng J., Willicut A., et al. TNF superfamily control of tissue remodeling and fibrosis. Front Immunol. 2023;14 doi: 10.3389/fimmu.2023.1219907. [DOI] [PMC free article] [PubMed] [Google Scholar]
46.Talamonti E., Pauter A.M., Asadi A., et al. Impairment of systemic DHA synthesis affects macrophage plasticity and polarization: implications for DHA supplementation during inflammation. Cell Mol Life Sci. 2017;74:2815–2826. doi: 10.1007/s00018-017-2498-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
47.Lee C., Kim J., Han J., et al. Formyl peptide receptor 2 determines sex-specific differences in the progression of nonalcoholic fatty liver disease and steatohepatitis. Nat Commun. 2022;13:578. doi: 10.1038/s41467-022-28138-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
48.Chen J., Austin-Williams S., O'Riordan C.E., et al. Formyl peptide receptor type 2 deficiency in myeloid cells amplifies sepsis-induced cardiac dysfunction. J Innate Immun. 2023;15:548–561. doi: 10.1159/000530284. [DOI] [PMC free article] [PubMed] [Google Scholar]
49.Tylek K., Trojan E., Regulska M., et al. Formyl peptide receptor 2, as an important target for ligands triggering the inflammatory response regulation: a link to brain pathology. Pharmacol Rep. 2021;73:1004–1019. doi: 10.1007/s43440-021-00271-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
50.Shaker M.E. The contribution of sterile inflammation to the fatty liver disease and the potential therapies. Biomed Pharmacother. 2022;148 doi: 10.1016/j.biopha.2022.112789. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Multimedia component 1

mmc1.pdf^{(2.1MB, pdf)}

Multimedia component 2

mmc2.pdf^{(144.2KB, pdf)}

Multimedia component 3

mmc3.pdf^{(1.3MB, pdf)}

Multimedia component 4

mmc4.pdf^{(5.5MB, pdf)}

Data Availability Statement

All data are available from the corresponding authors upon reasonable request. The RNA-seq data have been deposited in the Gene Expression Omnibus (GSE232780, GSE263768, and GSE263770).

[bib1] 1.Loomba R., Friedman S.L., Shulman G.I. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell. 2021;184:2537–2564. doi: 10.1016/j.cell.2021.04.015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib2] 2.Le P., Tatar M., Dasarathy S., et al. Estimated burden of metabolic dysfunction-associated steatotic liver disease in US adults, 2020 to 2050. JAMA Netw Open. 2025;8 doi: 10.1001/jamanetworkopen.2024.54707. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib3] 3.Angulo P., Kleiner D.E., Dam-Larsen S., et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389–397. doi: 10.1053/j.gastro.2015.04.043. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib4] 4.Harrison S.A., Bedossa P., Guy C.D., et al. A Phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497–509. doi: 10.1056/NEJMoa2309000. [DOI] [PubMed] [Google Scholar]

[bib5] 5.Schuster S., Cabrera D., Arrese M., et al. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol. 2018;15:349–364. doi: 10.1038/s41575-018-0009-6. [DOI] [PubMed] [Google Scholar]

[bib6] 6.Huby T., Gautier E.L. Immune cell-mediated features of non-alcoholic steatohepatitis. Nat Rev Immunol. 2022;22:429–443. doi: 10.1038/s41577-021-00639-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib7] 7.Tsuchida T., Friedman S.L. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14:397–411. doi: 10.1038/nrgastro.2017.38. [DOI] [PubMed] [Google Scholar]

[bib8] 8.Anstee Q.M., Neuschwander-Tetri B.A., Wai-Sun Wong V., et al. Cenicriviroc lacked efficacy to treat liver fibrosis in nonalcoholic steatohepatitis: AURORA Phase III randomized study. Clin Gastroenterol Hepatol. 2024;22:124–134. doi: 10.1016/j.cgh.2023.04.003. [DOI] [PubMed] [Google Scholar]

[bib9] 9.Harrison S.A., Goodman Z., Jabbar A., et al. A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. J Hepatol. 2020;72:816–827. doi: 10.1016/j.jhep.2019.11.024. [DOI] [PubMed] [Google Scholar]

[bib10] 10.Serhan C.N. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510:92–101. doi: 10.1038/nature13479. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib11] 11.Serhan C.N., Levy B.D. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest. 2018;128:2657–2669. doi: 10.1172/JCI97943. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib12] 12.Li J., Deng X., Bai T., et al. Resolvin D1 mitigates non-alcoholic steatohepatitis by suppressing the TLR4-MyD88-mediated NF-kappaB and MAPK pathways and activating the Nrf2 pathway in mice. Int Immunopharmacol. 2020;88 doi: 10.1016/j.intimp.2020.106961. [DOI] [PubMed] [Google Scholar]

[bib13] 13.Sansbury B.E., Li X., Wong B., et al. Myeloid ALX/FPR2 regulates vascularization following tissue injury. Proc Natl Acad Sci U S A. 2020;117:14354–14364. doi: 10.1073/pnas.1918163117. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib14] 14.Tsuchida T., Lee Y.A., Fujiwara N., et al. A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. J Hepatol. 2018;69:385–395. doi: 10.1016/j.jhep.2018.03.011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib15] 15.Shi H., Wang X., Li F., et al. CD47-SIRPalpha axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis. Sci Transl Med. 2022;14 doi: 10.1126/scitranslmed.abp8309. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib16] 16.Rom O., Xu G., Guo Y., et al. Nitro-fatty acids protect against steatosis and fibrosis during development of nonalcoholic fatty liver disease in mice. EBioMedicine. 2019;41:62–72. doi: 10.1016/j.ebiom.2019.02.019. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib17] 17.Pant R., Kabeer S.W., Sharma S., et al. Pharmacological inhibition of DNMT1 restores macrophage autophagy and M2 polarization in Western diet-induced nonalcoholic fatty liver disease. J Biol Chem. 2023;299 doi: 10.1016/j.jbc.2023.104779. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib18] 18.Lei Z., Yu J., Wu Y., et al. CD1d protects against hepatocyte apoptosis in non-alcoholic steatohepatitis. J Hepatol. 2024;80:194–208. doi: 10.1016/j.jhep.2023.10.025. [DOI] [PubMed] [Google Scholar]

[bib19] 19.Das S., Finney A.C., Anand S.K., et al. Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis. Nat Metab. 2024;6:1939–1962. doi: 10.1038/s42255-024-01134-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib20] 20.Hatano E. Tumor necrosis factor signaling in hepatocyte apoptosis. J Gastroenterol Hepatol. 2007;22(Suppl 1):S43–S44. doi: 10.1111/j.1440-1746.2006.04645.x. [DOI] [PubMed] [Google Scholar]

[bib21] 21.Ioannou G.N., Haigh W.G., Thorning D., et al. Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis. J Lipid Res. 2013;54:1326–1334. doi: 10.1194/jlr.M034876. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib22] 22.Fredman G., Hellmann J., Proto J.D., et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun. 2016;7 doi: 10.1038/ncomms12859. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib23] 23.Yang L., Zhou X., Sun J., et al. Reactive oxygen species mediate anlotinib-induced apoptosis via activation of endoplasmic reticulum stress in pancreatic cancer. Cell Death Dis. 2020;11:766. doi: 10.1038/s41419-020-02938-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib24] 24.Sung H.J., Ma W., Wang P.Y., et al. Mitochondrial respiration protects against oxygen-associated DNA damage. Nat Commun. 2010;1:5. doi: 10.1038/ncomms1003. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib25] 25.Knupp J., Arvan P., Chang A. Increased mitochondrial respiration promotes survival from endoplasmic reticulum stress. Cell Death Differ. 2019;26:487–501. doi: 10.1038/s41418-018-0133-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib26] 26.Calderin E.P., Zheng J.J., Boyd N.L., et al. Exercise-induced specialized proresolving mediators stimulate AMPK phosphorylation to promote mitochondrial respiration in macrophages. Mol Metab. 2022;66 doi: 10.1016/j.molmet.2022.101637. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib27] 27.Hosseini Z., Marinello M., Decker C., et al. Resolvin D1 enhances necroptotic cell clearance through promoting macrophage fatty acid oxidation and oxidative phosphorylation. Arterioscler Thromb Vasc Biol. 2021;41:1062–1075. doi: 10.1161/ATVBAHA.120.315758. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib28] 28.Gaskell H., Ge X., Desert R., et al. Ablation of Hmgb1 in intestinal epithelial cells causes intestinal lipid accumulation and reduces NASH in mice. Hepatol Commun. 2020;4:92–108. doi: 10.1002/hep4.1448. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib29] 29.Kazankov K., Jorgensen S.M.D., Thomsen K.L., et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2019;16:145–159. doi: 10.1038/s41575-018-0082-x. [DOI] [PubMed] [Google Scholar]

[bib30] 30.Remmerie A., Martens L., Thone T., et al. Osteopontin expression identifies a subset of recruited macrophages distinct from Kupffer cells in the fatty liver. Immunity. 2020;53:641–657. doi: 10.1016/j.immuni.2020.08.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib31] 31.Guilliams M., Bonnardel J., Haest B., et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell. 2022;185:379–396. doi: 10.1016/j.cell.2021.12.018. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib32] 32.Daemen S., Gainullina A., Kalugotla G., et al. Dynamic shifts in the composition of resident and recruited macrophages influence tissue remodeling in NASH. Cell Rep. 2021;34 doi: 10.1016/j.celrep.2020.108626. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib33] 33.Han H., Ge X., Komakula S.S.B., et al. Macrophage-derived osteopontin (SPP1) protects from nonalcoholic steatohepatitis. Gastroenterology. 2023;165:201–217. doi: 10.1053/j.gastro.2023.03.228. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib34] 34.Brenner C., Galluzzi L., Kepp O., et al. Decoding cell death signals in liver inflammation. J Hepatol. 2013;59:583–594. doi: 10.1016/j.jhep.2013.03.033. [DOI] [PubMed] [Google Scholar]

[bib35] 35.Chiurchiu V., Leuti A., Dalli J., et al. Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses. Sci Transl Med. 2016;8:353ra111. doi: 10.1126/scitranslmed.aaf7483. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib36] 36.Trickett A., Kwan Y.L. T cell stimulation and expansion using anti-CD3/CD28 beads. J Immunol Methods. 2003;275:251–255. doi: 10.1016/s0022-1759(03)00010-3. [DOI] [PubMed] [Google Scholar]

[bib37] 37.Shi D., Li Y., Shi X., et al. Transcriptional expression of CXCL10 and STAT1 in lupus nephritis and the intervention effect of triptolide. Clin Rheumatol. 2023;42:539–548. doi: 10.1007/s10067-022-06400-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib38] 38.Naim A., Pan Q., Baig M.S. Matrix metalloproteinases (MMPs) in liver diseases. J Clin Exp Hepatol. 2017;7:367–372. doi: 10.1016/j.jceh.2017.09.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib39] 39.Fallowfield J.A., Mizuno M., Kendall T.J., et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol. 2007;178:5288–5295. doi: 10.4049/jimmunol.178.8.5288. [DOI] [PubMed] [Google Scholar]

[bib40] 40.Pellicoro A., Aucott R.L., Ramachandran P., et al. Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis. Hepatology. 2012;55:1965–1975. doi: 10.1002/hep.25567. [DOI] [PubMed] [Google Scholar]

[bib41] 41.Wang S., Li K., Pickholz E., et al. An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Sci Transl Med. 2023;15 doi: 10.1126/scitranslmed.add3949. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib42] 42.Ying H.Z., Chen Q., Zhang W.Y., et al. PDGF signaling pathway in hepatic fibrosis pathogenesis and therapeutics. Mol Med Rep. 2017;16:7879–7889. doi: 10.3892/mmr.2017.7641. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib43] 43.Seitz T., Hellerbrand C. Role of fibroblast growth factor signalling in hepatic fibrosis. Liver Int. 2021;41:1201–1215. doi: 10.1111/liv.14863. [DOI] [PubMed] [Google Scholar]

[bib44] 44.Wijeratne D., Rodger J., Stevenson A., et al. Ephrin-A2 affects wound healing and scarring in a murine model of excisional injury. Burns. 2019;45:682–690. doi: 10.1016/j.burns.2018.10.002. [DOI] [PubMed] [Google Scholar]

[bib45] 45.Steele H., Cheng J., Willicut A., et al. TNF superfamily control of tissue remodeling and fibrosis. Front Immunol. 2023;14 doi: 10.3389/fimmu.2023.1219907. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib46] 46.Talamonti E., Pauter A.M., Asadi A., et al. Impairment of systemic DHA synthesis affects macrophage plasticity and polarization: implications for DHA supplementation during inflammation. Cell Mol Life Sci. 2017;74:2815–2826. doi: 10.1007/s00018-017-2498-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib47] 47.Lee C., Kim J., Han J., et al. Formyl peptide receptor 2 determines sex-specific differences in the progression of nonalcoholic fatty liver disease and steatohepatitis. Nat Commun. 2022;13:578. doi: 10.1038/s41467-022-28138-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib48] 48.Chen J., Austin-Williams S., O'Riordan C.E., et al. Formyl peptide receptor type 2 deficiency in myeloid cells amplifies sepsis-induced cardiac dysfunction. J Innate Immun. 2023;15:548–561. doi: 10.1159/000530284. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib49] 49.Tylek K., Trojan E., Regulska M., et al. Formyl peptide receptor 2, as an important target for ligands triggering the inflammatory response regulation: a link to brain pathology. Pharmacol Rep. 2021;73:1004–1019. doi: 10.1007/s43440-021-00271-x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib50] 50.Shaker M.E. The contribution of sterile inflammation to the fatty liver disease and the potential therapies. Biomed Pharmacother. 2022;148 doi: 10.1016/j.biopha.2022.112789. [DOI] [PubMed] [Google Scholar]

PERMALINK

Resolvin D1-mediated cellular crosstalk protects against MASH

Amaia Navarro-Corcuera

Yiwei Zhu

Fanglin Ma

Neha Gupta

Haley Asplund

Bruno Cogliati

Jerry E Chipuk

Oren Rom

Scott L Friedman

Brian E Sansbury

Xin Huang

Bishuang Cai

Abstract

Background & aims

Methods

Results

Conclusions

Impact and implications

Graphical abstract

Highlights

Introduction

Materials and methods

Animal model

Human liver specimens

Study protocol

Results

RvD1-FPR2 signaling is impaired in human and mouse MASH livers

Fig. 1.

RvD1 administration mitigates MASH progression

Fig. 2.

RvD1 reduces cell death by suppressing the ROS-CHOP pathway in hepatocytes

Fig. 3.

scRNA-seq reveals the protective effect of RvD1 against immune cell activation

Fig. 4.

RvD1-mediated cellular crosstalk among hepatocytes, KCs, and T cells alleviates inflammation

Fig. 5.

RvD1 suppresses HSC activation and liver fibrosis in MASH

Fig. 6.

Discussion

Abbreviations

Financial support

Authors’ contributions

Data availability statement

Conflicts of interest

Acknowledgements

Footnotes

Contributor Information

Supplementary data

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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