Methyltransferase-like 3 (METTL3) Epigenetically Modulates Glutathione Peroxidase 4 (GPX4) Expression to Affect Asthma

Liangfeng Lin; Xiaohao Hu; Qiaoyu Li; Linlin Huang

doi:10.18502/ijaai.v22i6.14644

Liangfeng Lin Department of Pediatrics, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
Xiaohao Hu Department of Pediatrics, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
Qiaoyu Li Department of Pediatrics, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
Linlin Huang Department of Respiratory Medicine, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China

DOI: https://doi.org/10.18502/ijaai.v22i6.14644

Keywords: Asthma; Bronchial disease; Epithelial cells; Ferroptosis; Glutathione peroxidase 4; Methyltransferase-like protein 3, human; Oxidative stress; RNA stability

Abstract

Asthma, a prevalent chronic airway inflammatory condition, poses a significant health challenge. In this study, we delved into the regulatory mechanisms governing asthma, focusing on Methyltransferase-like 3 (METTL3).

Through an ovalbumin (OVA)-induced mouse model and interleukin-13 (IL-13)-induced cell model, we mimicked the in vivo and in vitro functions of METTL3 in asthma.

Our research revealed that METTL3 expression significantly decreased in asthma-induced mice and IL-13-stimulated cells compared to the control group. Moreover, METTL3 overexpression enhanced bronchial epithelial cell viability and proliferation. Mechanistically, we observed elevated levels of total iron, Fe²⁺, malondialdehyde (MDA), lipid reactive oxygen species (ROS), alongside reduced glutathione (GSH) levels in IL-13-stimulated cells. Remarkably, METTL3 overexpression counteracted these effects, suggesting a pivotal role in mitigating asthma-related oxidative stress. Furthermore, our study highlighted the involvement of N6-methyladenosine methylation (m6A) modification, where METTL3 regulated the m6A modification of glutathione peroxidase 4 (GPX4) RNA, impacting RNA stability. Knockdown of METTL3 suppressed m6A modification on GPX4 RNA, impairing its stability and contributing to IL-13-induced ferroptosis. Interestingly, METTL3 overexpression not only inhibited cell ferroptosis but also alleviated asthma symptoms.

Our findings shed light on the epigenetic regulation of asthma through METTL3-mediated m6A modification, offering potential therapeutic avenues for this prevalent inflammatory disease.