4-Octyl itaconate ameliorates cigarette smoke-induced chronic obstructive pulmonary disease by suppressing necroptosis in alveolar macrophages via Nrf2 activation
- 1The First school of Clinical Medicine, Lanzhou University
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.
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BibTeX
@article{wang20264octyl,
title = {{4-Octyl itaconate ameliorates cigarette smoke-induced chronic obstructive pulmonary disease by suppressing necroptosis in alveolar macrophages via Nrf2 activation}},
author = {Zhe Wang and Xiaofeng Li and Tingting Zhang and Ping Huang and Xichen Pang and Xiaoli Zeng and Xiaoju Liu},
journal = {Scientific Reports},
year = {2026},
month = jul,
doi = {10.1038/s41598-026-59351-8},
url = {https://doi.org/10.1038/s41598-026-59351-8},
note = {CC BY},
}
RIS
TY - JOUR
TI - 4-Octyl itaconate ameliorates cigarette smoke-induced chronic obstructive pulmonary disease by suppressing necroptosis in alveolar macrophages via Nrf2 activation
AU - Zhe Wang
AU - Xiaofeng Li
AU - Tingting Zhang
AU - Ping Huang
AU - Xichen Pang
AU - Xiaoli Zeng
AU - Xiaoju Liu
PY - 2026
DA - 2026/07/01
JO - Scientific Reports
DO - 10.1038/s41598-026-59351-8
UR - https://doi.org/10.1038/s41598-026-59351-8
AB - 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.
SN - 2045-2322
ER -