2. Academic Validation
  3. HnRNPA2B1 promotes cardiac ferroptosis via m6A-dependent stabilization of PFN2 mRNA in myocardial ischemia-reperfusion injury

HnRNPA2B1 promotes cardiac ferroptosis via m6A-dependent stabilization of PFN2 mRNA in myocardial ischemia-reperfusion injury

  • Free Radic Biol Med. 2025 May:232:231-243. doi: 10.1016/j.freeradbiomed.2025.02.038.
Shuotao Shi 1,  Qi Chen 1,  Ying Yang 1,  Zipei Li 1,  Ruiyan Zheng 1,  Rong Zhang 2,  Zhongqiu Liu 3,  Yuanyuan Cheng 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Traditional Chinese Medicine Syndrome, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
  • 2 State Key Laboratory of Traditional Chinese Medicine Syndrome, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China; Chinese Medicine Guangdong Laboratory, Guangdong Hengqin, Zhuhai, Guangdong, China.
  • 3 State Key Laboratory of Traditional Chinese Medicine Syndrome, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China; Chinese Medicine Guangdong Laboratory, Guangdong Hengqin, Zhuhai, Guangdong, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau. Electronic address: liuzq@gzucm.edu.cn.
  • 4 State Key Laboratory of Traditional Chinese Medicine Syndrome, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China. Electronic address: chengyuanyuan@gzucm.edu.cn.
PMID: 40010516 DOI: 10.1016/j.freeradbiomed.2025.02.038
Abstract

Myocardial ischemia-reperfusion damage (MIRI) is a clinical problem and lacks proven treatment approaches. As a m6A reader, hnRNPA2B1 controls RNA destiny in the pathophysiology of neurodegenerative and cancerous disorders. Recently, we found that the level of hnRNPA2B1 was elevated in patients with myocardial infarction after percutaneous coronary intervention (PCI), which was positively correlated with cTnI. However, the role of hnRNPA2B1 in MIRI is still unknown. In the present study, we investigated the mechanism underlying MIRI-induced Ferroptosis by focusing on a novel function of hnRNPA2B1. Our results showed that HnRNPA2B1 was also significantly increased in cardiomyocytes of MIRI models in vitro and in vivo. Genetically deleting hnRNPA2B1 effectively mitigated myocardial injury and cardiac function during MIRI. Silencing hnRNPA2B1 in cardiomyocytes boosted cell survival and decreased Ferroptosis by lowering lipid ROS, MDA, Fe2+, and raising GSH, FTH1 levels, while overexpressing hnRNPA2B1 had the opposite impact. Mechanistic investigations revealed that hnRNPA2B1 recognized and interacted with the m6A site of PFN2 mRNA at "AGACU" to enhance the stability of PFN2 mRNA transcripts. Furthermore, PFN2 knockdown resulted in decreased MDA and Fe2+ levels and an increase in FTH1 expression. Importantly, silencing PFN2 attenuated Ferroptosis in cardiomyocytes overexpressing hnRNPA2B1 during OGD/R injury. Collectively, hnRNPA2B1 potentially acts as a therapeutic target of MIRI through regulating caridac Ferroptosis mediated by m6A-PFN2/FTH1 pathway.

Keywords

Ferroptosis; Myocardial ischemia-reperfusion injury; hnRNPA2B1; profilin2.

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