FERPIR promotes cardiomyocyte survival and attenuates cardiac remodeling after myocardial infarction

PIWI-interacting RNAs (piRNAs) are widely expressed in cardiac tissues and play important roles in cardiac pathophysiology. However, their functions and molecular mechanisms in cardiac remodeling following myocardial infarction (MI) and cardiomyocyte ferroptosis remain largely unknown. Here, we identified a ferroptosis-related piRNA (FERPIR), which inhibits ischemia/reperfusion (I/R) induced myocardial injury, cardiac remodeling and ferroptosis by targeting HNRNPA2B1-dependent regulation of Fis1. FERPIR levels were decreased in hypoxia/reoxygenation (H/R)-exposed cardiomyocytes and I/R-injured mouse hearts. FERPIR prevented I/R-induced acute injury and pathological cardiac remodeling. In vitro, overexpression of FERPIR inhibits H/R-induced ferroptosis. Mechanistically, FERPIR directly bound to HNRNPA2B1 and promoted its stability, which exhibited decreased ferroptosis and improved cardiac function upon I/R injury. Fis1 acted as a downstream regulator of HNRNPA2B1, and FERPIR recruited HNRNPA2B1 to bind to Fis1 mRNA and decreased its stability, thereby inhibiting mitochondrial fission and ferroptosis, which improves cardiac remodeling after myocardial infarction. Our findings reveal that FERPIR prevents myocardial I/R induced injury and pathological cardiac remodeling through the HNPA2B1/Fis1 axis, which provides potential therapeutic targets against cardiac injury caused by cardiomyocyte ferroptosis.