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. 2024 Jun;18(3):499-515.
doi: 10.1007/s11684-023-1052-4. Epub 2024 May 28.

m6A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation

Han Wu #  1 , Weitao Jiang #  1 , Ping Pang #  1 , Wei Si  1 , Xue Kong  1 , Xinyue Zhang  1 , Yuting Xiong  1 , Chunlei Wang  1 , Feng Zhang  1 , Jinglun Song  1 , Yang Yang  1 , Linghua Zeng  1 , Kuiwu Liu  1 , Yingqiong Jia  1 , Zhuo Wang  1 , Jiaming Ju  1 , Hongtao Diao  2 , Yu Bian  3 , Baofeng Yang  4
Affiliations

m6A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation

Han Wu et al. Front Med. 2024 Jun.

Abstract

Cardiac fibrosis caused by ventricular remodeling and dysfunction such as post-myocardial infarction (MI) can lead to heart failure. RNA N6-methyladenosine (m6A) methylation has been shown to play a pivotal role in the occurrence and development of many illnesses. In investigating the biological function of the m6A reader YTHDF1 in cardiac fibrosis, adeno-associated virus 9 was used to knock down or overexpress the YTHDF1 gene in mouse hearts, and MI surgery in vivo and transforming growth factor-β (TGF-β)-activated cardiac fibroblasts in vitro were performed to establish fibrosis models. Our results demonstrated that silencing YTHDF1 in mouse hearts can significantly restore impaired cardiac function and attenuate myocardial fibrosis, whereas YTHDF1 overexpression could further enhance cardiac dysfunction and aggravate the occurrence of ventricular pathological remodeling and fibrotic development. Mechanistically, zinc finger BED-type containing 6 mediated the transcriptional function of the YTHDF1 gene promoter. YTHDF1 augmented AXL translation and activated the TGF-β-Smad2/3 signaling pathway, thereby aggravating the occurrence and development of cardiac dysfunction and myocardial fibrosis. Consistently, our data indicated that YTHDF1 was involved in activation, proliferation, and migration to participate in cardiac fibrosis in vitro. Our results revealed that YTHDF1 could serve as a potential therapeutic target for myocardial fibrosis.

Keywords: AXL; YTHDF1; ZBED6; cardiac fibrosis; heart failure.

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