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

The impact of fine particulate matter (PM 2.5 ) on respiratory health, especially in the context of asthma exacerbation, is a critical environmental concern. Our study delved into the molecular mechanisms by which PM 2.5 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 PM 2.5 . We further uncovered that PM 2.5 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 PM 2.5 levels, compared to summer when PM 2.5 levels are typically lower. Our findings underscore the potential of targeting m6A methylation and mitophagy as therapeutic strategies for asthma exacerbated by environmental pollution.