Protein YTHDF1 Drives Asthma by Harming Mitochondria and Cell Signaling

Allergic airway inflammation, commonly known as asthma, is a chronic respiratory condition characterized by airway hyperresponsiveness and inflammation. While various factors contribute to its pathogenesis, the role of mitochondrial dysfunction in exacerbating this inflammation is increasingly recognized. However, the precise molecular mechanisms linking specific RNA-binding proteins to mitochondrial health and inflammatory signaling in allergic airways remain unclear. This study addresses how the RNA-binding protein YTHDF1 contributes to mitochondrial dysfunction and allergic airway inflammation through interaction with the β-catenin/TCF4 signaling pathway.

The study revealed that YTHDF1 expression was significantly elevated in both asthmatic mouse models and allergen-stimulated human cells. Overexpression of YTHDF1 in mice led to a 43% increase in airway hyperresponsiveness and a 2.7-fold increase in inflammatory cell infiltration compared to controls. Mechanistically, YTHDF1 was found to induce mitochondrial dysfunction, evidenced by a 2.5-fold increase in reactive oxygen species (ROS) production and a 35% reduction in mitochondrial membrane potential. This effect was mediated through a direct interaction with β-catenin, leading to enhanced TCF4 transcriptional activity and a 60% upregulation of pro-inflammatory target genes. The most critical finding was that YTHDF1 directly promotes mitochondrial dysfunction and exacerbates allergic airway inflammation by activating the β-catenin/TCF4 signaling pathway, leading to a significant increase in inflammatory markers and airway hyperresponsiveness.