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

作者：Pang, Ping; Si, Wei; Wu, Han; Ju, Jiaming; Liu, Kuiwu; Wang, Chunlei; Jia, Yingqiong; Diao, Hongtao; Zeng, Linghua; Jiang, Weitao; Yang, Yang; Xiong, Yuting; Kong, Xue; Zhang, Zhengwei; Zhang, Feng; Song, Jinglun; Wang, Ning^*; Yang, Baofeng^*; Bian, Yu^*

来源：Antioxidants and Redox Signaling, 2023.

DOI：10.1089/ars.2023.0291

• ischemia-reperfusion injury
• YTHDF2
• ferroptosis
• reactive oxygen species
• oxidative stress

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.

• 单位
  哈尔滨医科大学; y