Work

FTO-ACKR3 Axis Regulates Polycyclic Aromatic Hydrocarbons-Induced Asthma Attacks via AhR-Mediated m 6 A RNA Methylation

Year: 2025

Type: article

Abstract: Airborne polycyclic aromatic hydrocarbons (PAHs) are increasingly linked to asthma onset and exacerbation, yet their molecular mechanisms remain unclear. Building on our previous finding that PM2.5 alters m6A RNA methylation, we hypothesized that PAHs drive asthma progression through epitranscriptomic regulation. Here, we show that PAH exposure aggravated lung injury, airway remodeling, and fibrosis while reducing global m6A levelsan effect reversed by AhR inhibition. Mechanistically, PAH-activated AhR suppressed transcription of the m6A demethylase FTO, leading to widespread hypomethylation. Reduced m6A deposition on ACKR3 mRNA enhanced its stability through IGF2BP1/2/3 binding, thereby increasing ACKR3 expression. Elevated ACKR3 promoted autophagy and inflammatory signaling in bronchial epithelial cells. Consistently, FTO-deficient mice displayed exacerbated airway inflammation, fibrosis, and ACKR3-driven autophagy. Moreover, PAHs activated the TNFα/NF-κB pathway, further amplifying autophagy and inflammation. Together, these findings define a previously unrecognized AhR-FTO-ACKR3 epitranscriptomic axis through which PAHs potentiate NF-κB signaling, autophagy, and airway injury, providing new mechanistic insight and potential therapeutic targets for pollution-driven asthma.

Source: Environment & Health

DOI: 10.1021/envhealth.5c00261