YTHDF2 Promotes Cardiac Ferroptosis via Degradation of SLC7A11 in Cardiac Ischemia-Reperfusion Injury

Aims: Myocardial ischemia-reperfusion (I/R) injury facilitates cardiomyocyte death and endangers human health. N6-methyladenosine (m6A) methylation plays a critical role in cardiovascular diseases. The m6A reader YTHDF2 identifies m6A-modified RNA and promotes target RNA degradation. Hence, we hypothesized that YTHDF2 affects I/R injury by regulating RNA stability. Results: Both mRNA and protein levels of YTHDF2 were upregulated in I/R mice and hypoxia-reoxygenation (H/R)-induced cardiomyocytes. Silencing of endogenous YTHDF2 abrogated cardiac dysfunction and lowered the infarct size in I/R mice, and forced expression of YTHDF2 aggravated these adverse pathological processes. Consistently, the protective effect of silencing YTHDF2 occurred in cardiomyocytes exposed to H/R and erastin. Furthermore, RNA-seq and RIP revealed that YTHDF2 recognized the m6A modification sites of the ferroptosis-related gene SLC7A11 mRNA to promote its degradation both in vivo and in vitro. Inhibition of SLC7A11 impaired cardiac function, increased infarct size, and the release of LDH in I/R mice after silencing YTHDF2. The beneficial effects of si-YTHDF2 on H/R injury were reversed by co-transfection with si-SLC7A11, which substantially exacerbated ferroptosis and the production of ROS. Innovation and conclusion: The cardioprotective effects of silencing YTHDF2 are accomplished by increasing SLC7A11 stability and expression and reducing ferroptosis, providing novel potential therapeutic targets for treating ischemic cardiac diseases.

Automated summary

YTHDF2 affects myocardial ischemia-reperfusion injury by regulating RNA stability. Silencing YTHDF2 protects cardiac function and reduces infarct size, while overexpressing YTHDF2 exacerbates pathological processes. RNA analysis reveals that YTHDF2 recognizes m6A modification sites to promote the degradation of SLC7A11. Inhibition of SLC7A11 impairs heart function, increases infarct size, and the release of LDH. These findings provide novel potential therapeutic targets for treating ischemic cardiac diseases.