RANKL blockade attenuates MASH by remodeling the hepatic immune microenvironment
Abstract
ObjectiveMetabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease worldwide and is largely driven by chronic inflammation and hepatic immune dysregulation. The receptor activator of nuclear factor-κB ligand (RANKL) is a master regulator of bone metabolism with emerging immunomodulatory functions. Although growing evidence links the RANK-RANKL-OPG axis to MASH pathophysiology, whether RANKL blockade attenuates MASH development remains unclear. This study therefore investigated the effects and underlying mechanisms of RANKL blockade in a mouse model of MASH.MethodsMale mice were fed a choline-deficient high-fat diet (CDHFD) for 16 weeks to induce MASH and were treated with the RANKL-neutralizing antibody IK22/5 (1, 4, or 8 mg/kg) or an IgG control. Metabolic parameters, liver histology, and biochemical markers were assessed. Hepatic immune-cell infiltration was analyzed using CIBERSORT-based deconvolution, and immune populations were characterized by flow cytometry. Transcriptomic profiling identified RANKL-regulated genes, followed by cross-species analysis using human MASH datasets.ResultsRANKL blockade dose-responsively improved glucose tolerance, hepatic steatosis, inflammation, and fibrosis. Transcriptomic analysis identified 48 genes that were dysregulated in MASH but reversed by RANKL blockade; these genes were enriched in lipid metabolism, immune regulation, and fibrosis pathways. Immune profiling revealed broad remodeling of the hepatic immune microenvironment: IK22/5 reduced CD11bhighF4/80+ monocyte-derived macrophages, CD86+ M1-like macrophages, CD3-NK1.1+ NK cells, and CD3+NK1.1+CD4-CD8- NKT-like cells, while increasing γδ T cells and preserving CD11bintF4/80+Tim4+ Kupffer cells. Immunofluorescence showed that RANKL blockade significantly reduced hepatic CD74+F4/80+ macrophages, together with decreased expression of other lipid-associated macrophage markers.ConclusionsOverall, these findings indicate that RANKL blockade attenuated MASH development and support RANKL as a potential immune–metabolic regulator, providing a preclinical rationale for further evaluation of RANKL-targeted strategies in clinically relevant models.
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BibTeX
@article{wang2026rankl,
title = {{RANKL blockade attenuates MASH by remodeling the hepatic immune microenvironment}},
author = {Junxue Wang and Ningjia Yang and Huixia Li and Sijia Dan and Hui Guo and Kexi Zha and Fangzhen Xia},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1901751},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901751},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - RANKL blockade attenuates MASH by remodeling the hepatic immune microenvironment
AU - Junxue Wang
AU - Ningjia Yang
AU - Huixia Li
AU - Sijia Dan
AU - Hui Guo
AU - Kexi Zha
AU - Fangzhen Xia
PY - 2026
DA - 2026/11/05
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1901751
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901751
AB - ObjectiveMetabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease worldwide and is largely driven by chronic inflammation and hepatic immune dysregulation. The receptor activator of nuclear factor-κB ligand (RANKL) is a master regulator of bone metabolism with emerging immunomodulatory functions. Although growing evidence links the RANK-RANKL-OPG axis to MASH pathophysiology, whether RANKL blockade attenuates MASH development remains unclear. This study therefore investigated the effects and underlying mechanisms of RANKL blockade in a mouse model of MASH.MethodsMale mice were fed a choline-deficient high-fat diet (CDHFD) for 16 weeks to induce MASH and were treated with the RANKL-neutralizing antibody IK22/5 (1, 4, or 8 mg/kg) or an IgG control. Metabolic parameters, liver histology, and biochemical markers were assessed. Hepatic immune-cell infiltration was analyzed using CIBERSORT-based deconvolution, and immune populations were characterized by flow cytometry. Transcriptomic profiling identified RANKL-regulated genes, followed by cross-species analysis using human MASH datasets.ResultsRANKL blockade dose-responsively improved glucose tolerance, hepatic steatosis, inflammation, and fibrosis. Transcriptomic analysis identified 48 genes that were dysregulated in MASH but reversed by RANKL blockade; these genes were enriched in lipid metabolism, immune regulation, and fibrosis pathways. Immune profiling revealed broad remodeling of the hepatic immune microenvironment: IK22/5 reduced CD11bhighF4/80+ monocyte-derived macrophages, CD86+ M1-like macrophages, CD3-NK1.1+ NK cells, and CD3+NK1.1+CD4-CD8- NKT-like cells, while increasing γδ T cells and preserving CD11bintF4/80+Tim4+ Kupffer cells. Immunofluorescence showed that RANKL blockade significantly reduced hepatic CD74+F4/80+ macrophages, together with decreased expression of other lipid-associated macrophage markers.ConclusionsOverall, these findings indicate that RANKL blockade attenuated MASH development and support RANKL as a potential immune–metabolic regulator, providing a preclinical rationale for further evaluation of RANKL-targeted strategies in clinically relevant models.
SN - 1664-3224
ER -