RNA Demethylase FTO Shields Heart Cells From Ischemia-Reperfusion Damage

Myocardial ischemia-reperfusion injury (MIRI) — the paradoxical worsening of heart damage when blood flow is restored after a blockage — remains a leading cause of cardiac morbidity with no specific approved therapy. Understanding its molecular drivers is therefore urgent. This study from Fujian Medical University Union Hospital investigated how the epitranscriptomic regulator FTO (fat mass and obesity-associated protein), an m6A RNA demethylase, participates in MIRI pathophysiology.

The team constructed two complementary injury models: an in vivo rat model using 30-minute left anterior descending coronary artery ligation followed by 2-hour reperfusion, and an in vitro H9C2 cardiomyocyte hypoxia/reoxygenation (H/R) model (12 h hypoxia, 24 h normoxia). FTO expression was measured at both mRNA and protein levels and found to be significantly reduced in both systems under injury conditions, establishing FTO loss as a feature of MIRI.

To assess FTO's functional role, the researchers overexpressed FTO using AAV9 viral vectors injected peri-infarction in rats, and plasmid transfection in cells. FTO overexpression substantially reduced reactive oxygen species (ROS) detected by DCFH-DA flow cytometry, elevated the antioxidant enzyme SOD2, and increased mitochondrial biogenesis markers TFAM and COXI — all at both mRNA and protein levels. Cardiac function assessed by echocardiography (EF and FS) improved, TTC staining showed reduced infarct area, and HE staining confirmed less histological damage in FTO-overexpressing animals.

To identify the downstream effector, the team performed RNA immunoprecipitation (RIP) and RNA pulldown assays, confirming that FTO directly interacts with PGC-1α mRNA — a master regulator of mitochondrial biogenesis and antioxidant defense. MeRIP-PCR demonstrated that m6A methylation on PGC-1α mRNA was elevated in H/R conditions and reduced by FTO overexpression. RNA stability assays showed that FTO overexpression prolonged PGC-1α mRNA half-life, while FTO knockdown accelerated its degradation. Collectively, these data establish that FTO demethylates PGC-1α mRNA, shielding it from m6A-mediated decay and thereby sustaining PGC-1α protein abundance.

The findings position FTO as a cardioprotective factor that operates through an FTO→m6A removal→PGC-1α mRNA stabilization→mitochondrial biogenesis and ROS suppression axis. This adds mechanistic nuance to the growing body of work on epitranscriptomics in heart disease and suggests that pharmacological or gene-based enhancement of FTO activity could be a viable therapeutic approach for limiting MIRI-associated damage.