METTL16 supports arginine biosynthesis and suppresses IL-1β production to attenuate allergic asthma

Allergic asthma is a common disease. We aimed to investigate the role of METTL16, an N6-methyladenosine (m6A) writer, in allergic asthma and epithelial homeostasis. Here we show that pulmonary METTL16 expression was decreased in patients with allergic asthma and in a murine model of allergic asthma, particularly in airway epithelial cells. Genetic depletion of Mettl16 enhanced type 2 cytokine production and exacerbated epithelial-to-mesenchymal transition (EMT), whereas lung-specific METTL16 overexpression attenuated allergic airway inflammation and remodeling. Mechanistically, METTL16 promoted epithelial arginine biosynthesis and thereby suppressed IL-1β production. Furthermore, loss of Mettl16 impaired m6A modification of Ass1 mRNA, and increased Ass1 expression was associated with arginine biosynthesis. Our findings identify METTL16 as a critical regulator of allergic asthma and suggest it as a potential therapeutic target. Airway profiling reveals reduced m6A modification and METTL16 expression in allergic asthma. METTL16 supports epithelial arginine biosynthesis and suppresses IL-1β production to limit airway inflammation and remodeling.