2. Academic Validation
  3. Fine particulate matter exacerbates asthma by activating STC2-mediated mitophagy through METTL3/YTHDF2-dependent m6A methylation

Fine particulate matter exacerbates asthma by activating STC2-mediated mitophagy through METTL3/YTHDF2-dependent m6A methylation

  • J Hazard Mater. 2025 Sep 5:495:138854. doi: 10.1016/j.jhazmat.2025.138854.
Yao Liu 1,  Guoping Li 1,  Anying Xiong 1,  Jiliu Liu 1,  Ruitong Zeng 1,  Lei Zhang 1,  Junyi Wang 1,  Manling Jiang 1,  Jie Gao 1,  Ying Xiong 2,  Xiang He 3
Affiliations

Affiliations

  • 1 Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu 610031, China; Department of Respiration, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610031, China.
  • 2 Department of Pulmonary and Critical Care Medicine, Sichuan Friendship Hospital, Chengdu 610000, China.
  • 3 Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu 610031, China; Department of Respiration, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610031, China; National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China. Electronic address: [email protected].
PMID: 40499413 DOI: 10.1016/j.jhazmat.2025.138854
Abstract

The impact of fine particulate matter (PM2.5) on respiratory health, especially in the context of asthma exacerbation, is a critical environmental concern. Our study delved into the molecular mechanisms by which PM2.5 intensified asthma in mice, with a particular focus on N6-methyladenosine (m6A) methylation, Mitophagy, and the regulatory roles of STC2 and SQSTM1. Utilizing single-cell RNA Sequencing (scRNA-seq), we identified significant changes in immune cell distribution and a notable decrease in epithelial cell numbers in asthmatic mice exposed to PM2.5. We further uncovered that PM2.5 exposure significantly increased m6A methylation in STC2 mRNA, leading to up-regulation of STC2 expression and activation of Mitophagy. Mechanistic investigations revealed that METTL3, a key methyltransferase, up-regulated STC2 through m6A-dependent mRNA stability and YTHDF2 binding. STC2, in turn, increased SQSTM1 levels by inhibiting proteasomal degradation, thereby enhancing mitochondrial Autophagy and asthma severity. Additionally, we collected peripheral blood samples from asthma patients across different seasons and found that serum concentrations of METTL3 and STC2 were significantly higher during winter, a period of high PM2.5 levels, compared to summer when PM2.5 levels are typically lower. Our findings underscore the potential of targeting m6A methylation and Mitophagy as therapeutic strategies for asthma exacerbated by environmental pollution.

Keywords

Asthma exacerbation; Mitophagy; PM(2.5); STC2; Ubiquitination; m6A methylation.

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