Attenuated FTO induces necroptosis of alveolar epithelium via the m6A/CYP1B1/ROS/MLKL axis to promote the aggravation of pulmonary emphysema.

Emphysema is a major phenotype of chronic obstructive pulmonary disease (COPD) and reflects sustained oxidative injury and defective alveolar repair in the distal lung. While cigarette smoke is the dominant environmental trigger, endogenous epithelial programs that restrain reactive oxygen species (ROS) and preserve alveolar integrity remain poorly defined in the adult lung parenchyma. Here we identify that fat mass and obesity-associated protein (FTO) as a redox-responsive regulator in the alveolar epithelium. FTO is predominantly expressed in alveolar type II (AT2) epithelial cells and is markedly reduced in both the epithelium of human COPD patients and the lungs of cigarette smoke-exposed mice. This reduction correlated with worse pulmonary function and was inversely associated with cumulative smoking burden in human. Global attenuation of FTO expression resulted in spontaneous emphysema and impaired lung mechanics in mice. Mechanistically, FTO deficiency promotes cytochrome P450 1B1 (CYP1B1) expression via increased m6A modification and mRNA stabilization, thereby enhancing ROS accumulation and activating the necroptotic effector mixed lineage kinase domain-like protein (MLKL). Genetic silencing of CYP1B1 or antioxidant treatment with N-acetylcysteine (NAC) attenuated ROS and necroptosis. Moreover, conditional deletion of FTO in AT2 cells exacerbated oxidative stress, phosphorylated-MLKL/MLKL levels, and emphysematous injury in mice, indicating spontaneous emphysema driven by necroptosis-effects that were further aggravated in a chronic cigarette smoke-induced COPD model. NAC treatment effectively alleviated the COPD-related deterioration caused by FTO deficiency in AT2 cells. Together, these findings define an alveolar epithelial FTO-m6A-CYP1B1-ROS-MLKL axis that links redox dysregulation to necroptotic cell death and alveolar destruction, and they nominate FTO as a tractable node for redox-targeted intervention in COPD-related emphysema.