{
  "abstract": "Background: Chronic radiation proctitis (CRP) represents a significant clinical challenge characterized by irreversible fibrosis and a lack of specific pharmacological interventions. This study aimed to elucidate the cellular mechanisms underlying impaired tissue repair to identify novel therapeutic targets.\n\nMethods: We employed an integrative framework combining machine learning with bulk and high-resolution single-cell transcriptomic profiling in a murine CRP model. Computational mechanistic analyses included regulon inference, cell-cell communication analysis, and single-cell virtual knockout simulation. The pro-fibrotic association of the identified macrophage subset was further examined using independent single-cell datasets from liver cirrhosis and idiopathic pulmonary fibrosis. Furthermore, structure-based virtual screening and molecular dynamics simulations were conducted to identify potential pharmacological modulators.\n\nResults: We identified Ms4a6c as a key candidate gene exclusively expressed in a distinct, hybrid-activation macrophage subpopulation associated with pro-fibrotic transcriptional programs. These macrophages showed predicted associations with fibrosis via Thbs1-Cd47 paracrine signaling interactions with fibroblasts, and SCENIC regulon analysis identified Cebpb as a candidate upstream transcriptional regulator. Cross-disease analysis in liver cirrhosis and idiopathic pulmonary fibrosis single-cell datasets indicated that Ms4a6c-high macrophage subsets are consistently associated with elevated epithelial-mesenchymal transition and TGF-β signaling activity, supporting a potentially conserved pro-fibrotic role across organ systems. Furthermore, single-cell virtual knockout simulation predicted that the computational depletion of Ms4a6c may reverse pro-fibrotic transcriptomic signatures. Additionally, molecular docking and dynamics simulations identified the mitochondrial-derived peptide MOTS-c as a top-ranking candidate predicted to target Ms4a6c.\n\nConclusions: This study highlights the potential pathogenic involvement of Ms4a6c+ macrophages and identifies the Cebpb-Ms4a6c-Thbs1-Cd47 axis as a candidate pro-fibrotic signaling cascade that may be conserved across multiple organ fibrosis models. We propose MOTS-c as a potential pharmacological agent for mitigating radiation-induced intestinal fibrosis, pending experimental validation.",
  "abstract_shown": true,
  "affiliations": [
    "Key Laboratory for Precision Digestive Surgery and Intestinal Homeostasis, Department of General Surgery, The Second Affiliated Hospital of Army Medical University"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Peng Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Wei Tao"
    },
    {
      "affs": [
        0
      ],
      "name": "Hong Wen"
    },
    {
      "affs": [
        0
      ],
      "name": "Kai Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Yuanyuan Fu"
    },
    {
      "affs": [
        0
      ],
      "name": "Yanze Kan"
    },
    {
      "affs": [
        0
      ],
      "name": "Teming Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhiqiang Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Weidong Xiao"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/f2gk4hbd4xfqh.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1907084",
  "fulltext_url": "https://europepmc.org/articles/PMC13713458",
  "id": "f2gk4hbd4xfqh",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1907084/full",
  "language": "eng",
  "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": [
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2741|Effects of Radiation Exposure"
    ]
  ],
  "openalex": "W7221792528",
  "pdf_url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1907084/pdf",
  "pmcid": "PMC13713458",
  "pmid": "42952740",
  "published": "2026-10-14",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/f2gk4hbd4xfqh.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:17Z",
      "native_id": "10.3389/fimmu.2026.1907084",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1907084/full"
    },
    {
      "first_seen": "2026-10-31T00:20:41Z",
      "native_id": "MED:42952740",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42952740"
    },
    {
      "first_seen": "2026-10-31T12:24:00Z",
      "native_id": "PMC13713458",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fimmu.2026.1907084"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2741|Effects of Radiation Exposure",
      "subfield": "imaging"
    }
  ],
  "title": "Integrative transcriptomic and computational analysis associates Ms4a6c+ macrophages with fibrosis in radiation proctitis and computationally nominates MOTS-c as a candidate modulator",
  "title_text": "Integrative transcriptomic and computational analysis associates Ms4a6c+ macrophages with fibrosis in radiation proctitis and computationally nominates MOTS-c as a candidate modulator",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:21:07Z",
  "url": "https://research.draconitic.com/paper/f2gk4hbd4xfqh",
  "venue": "Frontiers in Immunology",
  "versions": []
}