{
  "abstract": "Background: Pulmonary fibrosis (PF) is a progressive interstitial lung disease driven in part by epithelial–mesenchymal transition (EMT), but the upstream epithelial regulators remain undefined, and conventional screens rarely separate causal drivers from bystanders.\n\nMethods: We integrated interpretable machine learning (SHAP-interpreted LASSO across five transcriptomic cohorts), single-cell virtual gene knockout (VGKO), protein–protein docking with molecular dynamics, co-immunoprecipitation and surface plasmon resonance, a bleomycin mouse model, and loss-/gain-of-function studies in TGF-β1-stimulated BEAS-2B cells, complemented by AI-guided drug screening.\n\nResults: SHAP nominated MT2A as a positively weighted predictor broadly expressed across multiple cell subpopulations, and in silico knockout nominated S100A8 as its leading candidate downstream target, yielding a directional MT2A → S100A8 hypothesis. Docking and molecular dynamics predicted a stable MT2A – S100A8 complex, co-immunoprecipitation recovered both proteins from the same complex in cells, and surface plasmon resonance measured direct binding with an apparent dissociation constant of 88 ± 20 nM. MT2A and S100A8 were co-upregulated in fibrotic mouse lung. In epithelial cells, MT2A knockdown reduced S100A8 and reversed the EMT signature, whereas overexpression amplified it. Reciprocal epistasis placed S100A8 downstream of MT2A as its obligate effector: re-expressing S100A8 restored EMT in MT2A -depleted cells, and silencing S100A8 abolished the pro-fibrotic effect of MT2A overexpression. AI screening nominated BRD-K54403101 as a candidate MT2A binder.\n\nConclusion: We identify MT2A as broadly expressed across single-cell clusters and show that in bronchial epithelial cells MT2A sustains S100A8 , which is necessary and sufficient to drive the EMT program. The experimentally defined MT2A-S100A8 axis is a tractable target in pulmonary fibrosis.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital",
    "Department of Pulmonary Medicine, Xiangyang Hospital Affiliated to Hubei University of Chinese Medicine",
    "Hubei Provincial Clinical Research Center for Integrative Medicine in Cancer Green Therapy",
    "Department of Respiratory and Critical Care Medicine, Shandong University of Traditional Chinese Medicine Affiliated Hospital"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Rui Fan"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Ying Liu"
    },
    {
      "affs": [
        3
      ],
      "name": "Guodong Zang"
    },
    {
      "affs": [
        0
      ],
      "name": "Daowei Li"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1ysa2w1q216ax.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1920411",
  "fulltext_url": null,
  "id": "1ysa2w1q216ax",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1920411/full",
  "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": [
    [
      "openalex",
      "2740|Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis"
    ]
  ],
  "openalex": "W7223172552",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-22",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/1ysa2w1q216ax.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:17Z",
      "native_id": "10.3389/fimmu.2026.1920411",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1920411/full"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "issn:1664-3224",
      "subfield": "immunology"
    }
  ],
  "title": "Metallothionein-2A licenses an S100A8 alarmin program to drive epithelial-mesenchymal transition in pulmonary fibrosis",
  "title_text": "Metallothionein-2A licenses an S100A8 alarmin program to drive epithelial-mesenchymal transition in pulmonary fibrosis",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:17Z",
  "url": "https://research.draconitic.com/paper/1ysa2w1q216ax",
  "venue": "Frontiers in Immunology",
  "versions": []
}