Fto-mediated m⁶A demethylation of Lox drives atrial fibrosis and promotes atrial fibrillation in a murine model of hyperthyroidism

Hyperthyroidism is a risk factor for atrial fibrillation (AF), and N⁶-methyladenosine (m⁶A) RNA methylation is crucial in cardiovascular regulation. However, the role of Fto-mediated m⁶A demethylation in hyperthyroidism-related AF remains unclear.

We consecutively recruited 232 AF patients undergoing ablation, stratified into age-, gender-, and comorbidity-matched cohorts, 116 with manifest hyperthyroidism and 116 without manifest hyperthyroidism. Assessments included thyroid profiles, echocardiography, low-voltage area (LVA) mapping, and 1-year recurrence. T4-treated mice with cardiomyocyte-specific Fto knockout or AAV9-mediated Fto overexpression were used. Electrophysiological and structural properties were assessed via electrical mapping and echocardiography. Mechanisms were further investigated in neonatal rat atrial myocytes (NRAMs). The hyperthyroid group showed higher 1-year recurrence (19.8 vs. 5.2%, P < 0.001) and larger LVA (27.81 vs. 20.25%, P < 0.001). Hyperthyroidism independently predicted LVA expansion (odds ratio = 2.868, P < 0.001). In mice, Fto up-regulation increased atrial fibrosis and AF susceptibility, while its deletion attenuated T4-induced atrial fibrosis and AF. Wild-type Fto overexpression promoted AF via m⁶A-dependent enhancement of lysyl oxidase (Lox) expression. Studies in NRAMs demonstrated that Fto enhanced the transcription and translation of Lox by reducing m⁶A methylation on Lox mRNA. Lox inhibition with BAPN suppressed fibrosis and AF inducibility.

Hyperthyroidism promoted atrial arrhythmogenicity through Fto-mediated m⁶A demethylation of Lox, increasing Lox expression and atrial fibrosis. Targeting Fto-m⁶A-Lox may offer a novel therapy for hyperthyroidism-associated AF.