{
  "abstract": "Sepsis is a life-threatening inflammatory disorder characterized by immune dysregulation and organ failure, and while peptidylarginine deiminase-2 (PAD2) regulates immune responses via citrullination, its role in immunometabolism remains unclear. Here we identify a PAD2-dependent mechanism that impairs mitochondrial glutamine metabolism and macrophage polarization during sepsis. Through single-cell RNA sequencing of bronchoalveolar lavage fluid from septic mice, we found that Pad2 -/- promotes M2 macrophage polarization, reduces lung injury, and improves survival. Using mass spectrometry-based citrullinomics, we identified voltage-dependent anion channel-3 (VDAC3) as a PAD2 substrate, and further demonstrated that PAD2-mediated citrullination at residue R252 suppresses glutamine transport and α-ketoglutarate (α-KG) production, thereby impairing oxidative phosphorylation (OXPHOS) and M2 reprogramming. Notably, substitution of R252 with alanine recapitulated Pad2 -/-phenotypes, and consistent with this, Pad2 -/- mice exhibited enhanced OXPHOS, attenuated inflammation, and improved outcomes in a Pseudomonas aeruginosa-induced model of sepsis and lung injury. Collectively, these findings establish the PAD2-VDAC3-glutamine axis as a key immunometabolic checkpoint that links post-translational modification to mitochondrial metabolism and macrophage function, suggesting that targeting this pathway may offer a promising strategy to restore immune balance in sepsis.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Surgery, University of Michigan Health System, Ann Arbor, United States.",
    "Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.",
    "Department of Surgery, Division of Surgical Science, University of Virginia, Charlottesville, United States.",
    "Neuroscience Institute and Department of Neurosurgery, Baylor Scott & White Health, Temple, Texas, United States.",
    "Metware Biotechnology Inc., Woburn, MA, United States.",
    "Department of Neurosurgery, Baylor College of Medicine, Temple, Texas, United States.",
    "Texas A&M University Colleges of Medicine and Pharmacy, College Station, United States.",
    "Cancer Research Center and Department of Internal Medicine, Dell Medical School, the University of Texas at Austin, Austin, Texas, United States."
  ],
  "article_type": "research support, u.s. gov't, p.h.s.",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Liujiazi Shao"
    },
    {
      "affs": [
        0
      ],
      "name": "Chao Quan"
    },
    {
      "affs": [
        0
      ],
      "name": "Tao Dong"
    },
    {
      "affs": [
        2
      ],
      "name": "Yuchen Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Xin Yu"
    },
    {
      "affs": [
        0
      ],
      "name": "Wenlu Ouyang"
    },
    {
      "affs": [
        3
      ],
      "name": "Dan Qi"
    },
    {
      "affs": [
        4
      ],
      "name": "Jeffrey Chu"
    },
    {
      "affs": [
        3,
        5,
        6,
        7
      ],
      "name": "Erxi Wu"
    },
    {
      "affs": [
        2
      ],
      "name": "Zequan Yang"
    },
    {
      "affs": [
        2
      ],
      "name": "Jianjie Ma"
    },
    {
      "affs": [
        0
      ],
      "name": "Yongqing Li"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/52mwfs3qy6fnk.bib",
  "cited_by": 0,
  "doi": "10.7150/ijbs.126368",
  "fulltext_url": "https://europepmc.org/articles/PMC13685606",
  "id": "52mwfs3qy6fnk",
  "issns": [
    "1449-2288"
  ],
  "landing_url": "https://europepmc.org/article/MED/42910200",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Mitochondrial Function and Pathology"
    ]
  ],
  "openalex": "W7214673201",
  "pdf_url": "https://europepmc.org/articles/PMC13685606?pdf=render",
  "pmcid": "PMC13685606",
  "pmid": "42910200",
  "published": "2026-09-11",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/52mwfs3qy6fnk.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:14Z",
      "native_id": "MED:42910200",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42910200"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Mitochondrial Function and Pathology",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Citrullination of VDAC3 by PAD2 restricts mitochondrial metabolism and suppresses macrophage reprogramming in sepsis.",
  "title_text": "Citrullination of VDAC3 by PAD2 restricts mitochondrial metabolism and suppresses macrophage reprogramming in sepsis.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:14Z",
  "url": "https://research.draconitic.com/paper/52mwfs3qy6fnk",
  "venue": "International journal of biological sciences",
  "versions": []
}