FGF21 blunts cardiac ischemia/ reperfusion injury by promoting autophagic flux via Stat1/Irgm1 pathway

Fibroblast growth factor 21 (FGF21), as a key metabolic hormone in the control of fatty acid and glucose metabolism, has been shown to be a potent cardioprotective agent against cardiovascular diseases. Here, in myocardial ischemia/reperfusion (I/R) model mice, we demonstrated that FGF21 alleviated myocardial I/R injury, while FGF21 knockout exacerbated this injury. Mechanistically, FGF21 can improve myocardial autophagic flux by regulating autophagosome processing, thereby alleviating myocardial injury. Furthermore, the downregulation of IRGM1 in FGF21-/- mice during I/R was associated with increased impairment of autophagic flux and autophagosome processing, which could be rescued by rhFGF21 via regulating Irgm1 expression. Meanwhile, the beneficial effect of rhFGF21 was limited in Irgm1 knockdown neonatal rat cardiomyocytes. Collectively, FGF21 knockout exacerbates myocardial I/R injury by intensifying the impairment of autophagic flux through Irgm1 signaling pathway. Activating FGF21 or Irgm1 might thus serve as promising therapeutic option to rescue myocardial I/R injury.