Fat mass and obesity-associated protein inhibits macrophage-mediated inflammation via the m6A demethylation of c-Jun in COPD

Abstract

Fat mass and obesity-associated protein (FTO), which is a key regulator of N6-methyladenosine (m6A) RNA modification, is associated with inflammatory processes. Chronic obstructive pulmonary disease (COPD) is a prevalent inflammatory disease that affects airways. However, the precise mechanism underlying the FTO-mediated regulation of inflammation in COPD remains unclear. This study aimed to investigate the molecular mechanisms through which FTO-mediated m6A RNA demethylation regulates macrophage-driven inflammation in COPD. Bioinformatics analysis of a GEO dataset (GSE148004) and validation in lung tissues revealed significant downregulation of FTO expression in patients with COPD (n = 10). Consistent with these findings, decreased FTO protein levels and a significant increase in global m6A methylation were observed in CSE-stimulated U937-derived macrophages (n = 3) and alveolar macrophages from mice with COPD (n = 6). Additionally, FTO overexpression attenuated CSE-induced IL-6 and TNF-α production by U937-derived macrophages (n = 3), and this overexpression alleviated emphysematous changes and airway inflammation in mice with COPD (n = 6). Moreover, RNA sequencing analysis revealed c-Jun as a downstream target of FTO. Mechanistically, FTO suppressed the m6A modification of c-Jun mRNA, leading to increased c-Jun mRNA degradation, thereby attenuating macrophage-mediated inflammatory responses (n = 3). Thus, FTO negatively regulates macrophage-driven inflammation in COPD by promoting the m6A demethylation and destabilization of c-Jun mRNA. These findings indicate that FTO may represent a promising therapeutic target for mitigating inflammation in patients with COPD.