{
  "abstract": "Background: Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disorder characterized by persistent oxidative stress and macrophage-driven airway injury. However, the molecular mechanisms linking mitochondrial dysfunction to innate immune activation in COPD remain unclear.\n\nMethods: Using a combination of in vitro and in vivo models, we investigated the role of CDGSH iron–sulfur domain-containing protein 1 (CISD1) in regulating macrophage inflammation and its crosstalk with epithelial cells. Transcriptomic, proteomic, and metabolomic analyses were performed to elucidate the molecular networks downstream of CISD1. Co-immunoprecipitation, ubiquitination assays, and confocal imaging were used to characterize the interaction between CISD1, STING, and the E3 ligase Ubr5.\n\nResults: Our previous study demonstrated that CSE downregulated CISD1 expression in macrophages. Based on this finding, we hypothesized that CISD1 might modulate STING activation and its downstream signaling pathways. Experimental validation confirmed that CISD1 downregulation indeed enhanced STING phosphorylation and activated the TBK1–IRF3–NF-KB pathway. Overexpression of CISD1 suppressed STING activation, type I interferon (IFN-b) production, and pro-inflammatory cytokine expression. Mechanistically, CISD1 directly interacted with STING and recruited Ubr5 to promote K48-linked ubiquitination and proteasomal degradation of STING, thereby restraining excessive innate immune signaling. Metabolomic profiling further revealed that CISD1 deficiency reduced intracellular daidzein, a key anti-inflammatory metabolite. Supplementation with daidzein attenuated NF-KB activation, restored antioxidant signaling, and alleviated epithelial apoptosis both in vitro and in COPD mouse models.\n\nConclusion: Our results support a model in which CISD1 restrains STING-dependent innate immune activation by recruiting Ubr5 to catalyze ubiquitination and proteasomal turnover of STING, thereby dampening macrophage inflammation and preserving epithelial integrity under cigarette smoke exposure. This CISD1-dependent innate immune checkpoint mechanistically links macrophage metabolic regulation to macrophage–epithelial crosstalk in COPD and identifies the CISD1–Ubr5–STING pathway—and daidzein restoration—as testable therapeutic hypotheses.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12931-026-03917-7.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Respiratory and Critical Care Medicine of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, 180 Fenglin Road, Shanghai, 200032 China",
    "Department of Pulmonary and Critical Care Medicine, Xinhua Hospital, Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092 China",
    "Datuan Community Health Service Center, 169 Yongding South Road, Pudong New Area, Shanghai, 201311 China",
    "Research Center of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032 China",
    "Department of Respiratory and Critical Care Medicine, Pudong Hospital, Fudan University, 2800 Road Gongwei Road, Shanghai, 201300 China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jiameng Gao"
    },
    {
      "affs": [
        1
      ],
      "name": "Fengfeng Han"
    },
    {
      "affs": [
        2
      ],
      "name": "Lili Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhilong Jiang"
    },
    {
      "affs": [
        0
      ],
      "name": "Fang Wang"
    },
    {
      "affs": [
        3
      ],
      "name": "Zhihui Min"
    },
    {
      "affs": [
        0
      ],
      "name": "Yuhao Qian"
    },
    {
      "affs": [
        4
      ],
      "name": "Yao Shen"
    },
    {
      "affs": [
        1
      ],
      "name": "Zhihong Chen"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cesp1q07kwfqp.bib",
  "cited_by": 0,
  "doi": "10.1186/s12931-026-03917-7",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13733169/",
  "id": "cesp1q07kwfqp",
  "issns": [
    "1465-9921",
    "1465-993X"
  ],
  "landing_url": "https://doi.org/10.1186/s12931-026-03917-7",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "lcc",
      "RC705-779"
    ],
    [
      "openalex",
      "2740|Chronic Obstructive Pulmonary Disease (COPD) Research"
    ]
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  "openalex": "W7221504557",
  "pdf_url": null,
  "pmcid": "PMC13733169",
  "pmid": "42983505",
  "published": "2026-10-01",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/cesp1q07kwfqp.ris",
  "sources": [
    {
      "first_seen": "2026-11-08T12:23:01Z",
      "native_id": "PMC13733169",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s12931-026-03917-7"
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    {
      "first_seen": "2026-11-08T14:21:02Z",
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Chronic Obstructive Pulmonary Disease (COPD) Research",
      "subfield": "general"
    }
  ],
  "title": "CISD1 suppresses COPD inflammation by recruiting ubiquitinated STING and altering macrophage metabolism",
  "title_text": "CISD1 suppresses COPD inflammation by recruiting ubiquitinated STING and altering macrophage metabolism",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T14:21:21Z",
  "url": "https://research.draconitic.com/paper/cesp1q07kwfqp",
  "venue": "Respiratory Research",
  "versions": []
}