{
  "abstract": "Cigarette smoke (CS)-induced necroptosis of alveolar macrophages (AMs) is critical in chronic obstructive pulmonary disease (COPD) pathogenesis. The itaconate derivative 4-octyl itaconate (4-OI) is a macrophage immunomodulator; however, its effects on AMs in COPD remain unclear. In this study, a COPD mouse model was established via CS exposure, and a murine alveolar macrophage (MH-S) cell model was generated via cigarette smoke extract (CSE) stimulation to investigate the protective effects of 4-OI and elucidate the underlying mechanisms. In vivo, CS exposure induced lung dysfunction, airway inflammation, and emphysema, which were significantly ameliorated by 4-OI administration. Furthermore, CS exposure upregulated the necroptosis-related proteins RIPK1, RIPK3, MLKL, and p-MLKL in lung tissue and triggered the excessive extracellular release of HMGB1, all of which were suppressed by 4-OI. In vitro, 4-OI inhibited CSE-induced necroptosis and the release of cytokines from AMs. Mechanistically, Nrf2 pathway-mediated antioxidant defenses were impaired in the lungs of COPD model mice and in CSE-stimulated AMs, and 4-OI partially restored antioxidant protein activity. Critically, pharmacological inhibition with ML385 or shRNA-mediated genetic knockdown of Nrf2 reversed the protective effects of 4-OI against CSE-induced necroptosis in AMs. In conclusion, 4-OI ameliorates CS-induced COPD by alleviating necroptosis in AMs, which depends on Nrf2 antioxidant pathway activation.",
  "abstract_shown": true,
  "affiliations": [
    "The First school of Clinical Medicine, Lanzhou University"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Zhe Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaofeng Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Tingting Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Ping Huang"
    },
    {
      "affs": [
        0
      ],
      "name": "Xichen Pang"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaoli Zeng"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaoju Liu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/06h1rh5wey1dd.bib",
  "cited_by": 1,
  "doi": "10.1038/s41598-026-59351-8",
  "fulltext_url": "https://doi.org/10.1038/s41598-026-59351-8",
  "id": "06h1rh5wey1dd",
  "issns": [
    "2045-2322"
  ],
  "landing_url": "https://doi.org/10.1038/s41598-026-59351-8",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "Q"
    ],
    [
      "lcc",
      "R"
    ],
    [
      "openalex",
      "2740|Chronic Obstructive Pulmonary Disease (COPD) Research"
    ]
  ],
  "openalex": "W7167101489",
  "pdf_url": "https://www.nature.com/articles/s41598-026-59351-8_reference.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-07-01",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/06h1rh5wey1dd.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:45:57Z",
      "native_id": "65d3a5232e104223a247192196c5c180",
      "source": "doaj",
      "url": "https://doi.org/10.1038/s41598-026-59351-8"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Chronic Obstructive Pulmonary Disease (COPD) Research",
      "subfield": "general"
    }
  ],
  "title": "4-Octyl itaconate ameliorates cigarette smoke-induced chronic obstructive pulmonary disease by suppressing necroptosis in alveolar macrophages via Nrf2 activation",
  "title_text": "4-Octyl itaconate ameliorates cigarette smoke-induced chronic obstructive pulmonary disease by suppressing necroptosis in alveolar macrophages via Nrf2 activation",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:45:57Z",
  "url": "https://research.draconitic.com/paper/06h1rh5wey1dd",
  "venue": "Scientific Reports",
  "versions": []
}