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<p>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.</p>

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4-Octyl itaconate ameliorates cigarette smoke-induced chronic obstructive pulmonary disease by suppressing necroptosis in alveolar macrophages via Nrf2 activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Zhe Wang,
  • Xiaofeng Li,
  • Tingting Zhang,
  • Ping Huang,
  • Xichen Pang,
  • Xiaoli Zeng,
  • Xiaoju Liu

摘要

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.