Work

YTHDC1-mediated m6A modification of PDK1 contributes to the epithelial-mesenchymal transition in smoking-induced COPD airway remodeling through lactate-induced MTA2 K539 lactylation

Year: 2025

Type: article

Abstract: Cigarette smoke (CS) is the main risk factor for chronic obstructive pulmonary disease (COPD), which is characterized by airway remodeling, a process that is associated with the epithelial-mesenchymal transition (EMT). Evidence for the involvement of N6-methyladenosine (m6A) modifications in the progression of COPD has emerged. However, the role of YTHDC1, an m6A reader, in airway remodeling remains elusive. Herein, we demonstrated that YTHDC1 drives the EMT through PDK1-mediated glycolytic reprogramming, resulting in airway remodeling in lungs of COPD animals. Mechanistically, in the airway epithelium, YTHDC1 recognizes and enhances the stability of PDK1 mRNA in an m6A-dependent manner. Elevated protein levels of PDK1 promote glycolytic reprogramming and lactate production. Additionally, lactate-induced lactylation of MTA2 enhances its protein stability, thereby contributing to the EMT. Moreover, we demonstrated, with an experimental model of COPD, that targeting of YTHDC1 attenuated the cigarette smoke-induced EMT of airway epithelium cells, which diminished airway remodeling in the lungs of COPD mice. For COPD patients, elevated levels of PDK1 and MTA2 were associated with elevated levels of YTHDC1. Overall, the present study revealed a mechanism for YTHDC1-mediated glycolysis reprogramming in the pathogenesis of airway remodeling and indicated that YTHDC1 could serve as a therapeutic target for COPD. In airway epithelial cells, exposure to CS causes an elevation of YTHDC1, which increases the stability and levels of PDK1 in an m6A-dependent manner. Elevated PDK1 drives glycolytic reprogramming and lactate accumulation. Lactate-induced MTA2 K539 lactylation, which enhances its protein stability, triggers the EMT, and results in airway remodeling, thus contributing to the pathogenesis of smoking-related COPD. • YTHDC1 drives glycolytic reprogramming and EMT in airway epithelial cells. • YTHDC1 regulates PDK1 in an m6A-dependent manner, leading to lactate accumulation. • Lactylation of MTA2 at K539 is involved in the CSE-induced EMT in airway epithelial cells. • Silencing of YTHDC1 alleviates airway remodeling in experimental COPD model.

Source: Environmental Technology & Innovation

DOI: 10.1016/j.eti.2025.104715