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  3. α-Tocopherol ameliorates allergic airway inflammation by regulating ILC2 ferroptosis in an LKB1-dependent manner

α-Tocopherol ameliorates allergic airway inflammation by regulating ILC2 ferroptosis in an LKB1-dependent manner

  • Mol Ther. 2025 Dec 3;33(12):6518-6536. doi: 10.1016/j.ymthe.2025.08.053.
Xiaogang Zhang 1,  Jingping Liu 2,  Ziyang Chen 3,  Suizi Zhou 4,  Tianci Wang 5,  Ruofan Yang 4,  Zhenchao Zhu 4,  Qianhui Qiu 6,  Yuxiong Guo 7,  Yumei He 8
Affiliations

Affiliations

  • 1 Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Department of Immunology, School of Basic Medical Sciences, Department of Clinical Laboratory, the Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou 510515, China; Department of Immunology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles, Southern Medical University, Guangzhou 510515, China.
  • 2 Department of Clinical Laboratory, the Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou 510000, China.
  • 3 Department of Immunology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles, Southern Medical University, Guangzhou 510515, China; Department of Neurosurgery, Guangdong Sanjiu Brain Hospital, Guangzhou 510515, China.
  • 4 Department of Otolaryngology-Head and Neck Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510515, China.
  • 5 Department of Immunology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles, Southern Medical University, Guangzhou 510515, China.
  • 6 Department of Otolaryngology-Head and Neck Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
  • 7 Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China. Electronic address: [email protected].
  • 8 Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Department of Immunology, School of Basic Medical Sciences, Department of Clinical Laboratory, the Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou 510515, China; Department of Immunology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
PMID: 40898617 DOI: 10.1016/j.ymthe.2025.08.053
Abstract

Dietary immunization plays a pivotal role in modulating allergic airway inflammation mediated by group 2 innate lymphoid cells (ILC2s). This study identifies α-tocopherol (α-Toc), a component of vitamin E, as a key regulator of allergic airway inflammation. Transcriptomic analysis of lung ILC2s from mice treated with α-Toc reveals reduced expression of scavenger receptor class B type 1 (SCARB1) and inhibition of the liver kinase B1 (LKB1)-AMPK/mTOR signaling pathway. Mice lacking LKB1 or treated with a SCARB1 antagonist demonstrate a significant reduction in ILC2 abundance, impaired ILC2 functionality, and diminished lung inflammation. Importantly, α-Toc fails to alleviate allergic airway inflammation in LKB1-deficient mice. Mechanistically, LKB1 deficiency reduces lung inflammation by promoting Ferroptosis in ILC2s. Specifically, LKB1 regulates the expression of the Krüppel-like Factor 4-glutathione peroxidase 4 complex, which is crucial for modulating ILC2 Ferroptosis and allergic airway inflammation. ILC2 activation and LKB1-mediated Ferroptosis were also observed in patients with asthma. In ex vivo cultures of human blood ILC2s, α-Toc treatment significantly inhibited ILC2 activation and LKB1-mediated Ferroptosis. These findings enhance our understanding of dietary immunization and suggest potential therapeutic applications for α-Toc in asthma management.

Keywords

GPX4; LKB1; allergic airway inflammation; asthma; ferroptosis; group 2 innate lymphoid cells; α-tocopherol.

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