FTO Alleviates COPD Pathogenesis by Demethylating S100A9 to Suppress ERK1/2-Drp1-Driven Mitophagy.

RATIONALE: N6-methyladenosine (m6A) modifications are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), yet the precise role of the demethylase fat mass and obesity-associated protein (FTO) remains unclear. OBJECTIVES: To identify whether FTO acts as a suppressor of COPD pathogenesis and to elucidate the underlying epitranscriptomic mechanism. METHODS: COPD models were established using cigarette smoke-exposed mice and cigarette smoke extract-stimulated BEAS-2B cells. FTO expression was modulated by lentiviral transduction. m6A epitranscriptomic microarray, RNA immunoprecipitation, m6A methylation analysis, and mRNA stability assays were performed. Inflammation, oxidative stress, mitophagy, and ERK1/2-Drp1 signaling were assessed. RESULTS: FTO expression is reduced in COPD patients and murine models, correlating with elevated m6A levels and disease severity. Overexpression of FTO mitigates inflammation, oxidative stress, and mitochondrial dysfunction by destabilizing S100 calcium-binding protein A9 (S100A9) mRNA via m6A demethylation. Mechanistically, FTO inhibits the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2)- dynamin-related protein 1 (Drp1), thereby suppressing excessive mitophagy and preserving mitochondrial integrity. Notably, S100A9 overexpression abolishes the protective effects of FTO, establishing the FTO/S100A9 axis as a central regulator. CONCLUSIONS: FTO attenuates COPD pathogenesis by demethylating S100A9 mRNA, thereby suppressing ERK1/2-Drp1-driven mitophagy. The FTO/S100A9 axis represents a novel epitranscriptomic mechanism and a potential therapeutic target for COPD.