{
  "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.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "Original Research",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "name": "Junxue Wang"
    },
    {
      "name": "Ningjia Yang"
    },
    {
      "name": "Huixia Li"
    },
    {
      "name": "Sijia Dan"
    },
    {
      "name": "Hui Guo"
    },
    {
      "name": "Kexi Zha"
    },
    {
      "name": "Fangzhen Xia"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6vgd27ccvd2ek.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1901751",
  "fulltext_url": null,
  "id": "6vgd27ccvd2ek",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901751",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "feed-journal",
      "biology/immunology"
    ]
  ],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-05",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/6vgd27ccvd2ek.ris",
  "sources": [
    {
      "first_seen": "2026-11-05T06:20:17Z",
      "native_id": "10.3389/fimmu.2026.1901751",
      "source": "feed-frontiers",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901751"
    },
    {
      "first_seen": "2026-11-05T12:21:11Z",
      "native_id": "10.3389/fimmu.2026.1901751",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901751/full"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "feed-journal:biology/immunology",
      "subfield": "immunology"
    }
  ],
  "title": "RANKL blockade attenuates MASH by remodeling the hepatic immune microenvironment",
  "title_text": "RANKL blockade attenuates MASH by remodeling the hepatic immune microenvironment",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T00:21:16Z",
  "url": "https://research.draconitic.com/paper/6vgd27ccvd2ek",
  "venue": "Frontiers in Immunology",
  "versions": []
}