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N6-methyladenosine (m6A) reader YTHDF2 accelerates endothelial cells ferroptosis in cerebrovascular atherosclerosis

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Abstract

Cerebrovascular diseases have extreme high mortality and disability rate worldwide, and endothelial cells injury-induced atherosclerosis acts as the main cause of cerebrovascular disease. Ferroptosis is a novel type of programmed cell death depending on iron-lipid peroxidation. Recent studies have revealed that ferroptosis might promote the progression of atherosclerosis (AS). Here, this research aimed to investigate the function and its profound mechanism on vascular endothelial cells in atherosclerosis. Research results revealed that YTHDF2 expression up-regulated in ox-LDL treated human umbilical vein endothelial cells (HUVECs). Gain/loss functional assays indicated that YTHDF2 overexpression inhibited HUVECs’ proliferation and accelerated the ferroptosis in ox-LDL-administered HUVECs. Meanwhile, YTHDF2 silencing promoted cell proliferation and reduced the ferroptosis in ox-LDL-administered HUVECs. Mechanistically, in silico analysis suggested that there were potential m6A-modified sites on SLC7A11 mRNA, and YTHDF2 could bind with SLC7A11 mRNA via m6A-dependent manner. YTHDF2 promoted the degradation of SLC7A11 mRNA, thereby reducing its mRNA stability. Taken together, these findings suggest that YTHDF2 accelerates endothelial cells ferroptosis in cerebrovascular atherosclerosis, hel** us enhance our comprehension on cerebrovascular disease pathological physiology.

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  1. Jia Li and Changlin Zou are both first author.

Authors and Affiliations

  1. Department of Surgery, Tian** Nankai Hospital, Tian** Medical University, No. 6 Changjiang Road, Tian**, 300100, China

    Jia Li, Changlin Zou, Zhiming Zhang & Feng Xue

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Jia Li, Changlin Zou, Zhiming Zhang performed the assays and wrote the main manuscript and prepared figures 1-5. Feng Xue was responsible for the funding. All authors reviewed the manuscript.

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Correspondence to Changlin Zou.

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Li, J., Zou, C., Zhang, Z. et al. N6-methyladenosine (m6A) reader YTHDF2 accelerates endothelial cells ferroptosis in cerebrovascular atherosclerosis. Mol Cell Biochem (2023). https://doi.org/10.1007/s11010-023-04858-1

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