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N6-methyladenosine writer METTL3 accelerates the sepsis-induced myocardial injury by regulating m6A-dependent ferroptosis

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Abstract

Ferroptosis is an iron-dependent and phospholipid peroxidation-mediated cell death, which has been identified to be involved in sepsis-induced injury. However, the in-depth molecular mechanisms of N6-methyladenosine (m6A) and ferroptosis on sepsis-induced myocardial injury are still unclear. Here, in the septic myocardial injury, m6A methyltransferase METTL3 level and methylation level high-expressed in lipopolysaccharide (LPS)-induced cardiomyocytes (H9C2). Functionally, METTL3 silencing repressed the ferroptosis phenotype induced by LPS. Mechanistically, METTL3-mediated m6A methylation on solute carrier family 7 member 11 (SLC7A11) empowered its mRNA with high methylation level. Moreover, YTHDF2 directly bound to the m6A modification sites of SLC7A11 to mediate the mRNA degradation. The m6A modified SLC7A11 mRNA was recognized by YTHDF2, which promoted the decay of SLC7A11 mRNA, consequently up-regulating ferroptosis in sepsis-induced myocardial injury. Together, these findings establish a role of METTL3 in the ferroptosis of LPS-induced cardiomyocytes, and provide potential therapeutic target to treat the sepsis-induced myocardial injury.

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Funding

This work was supported by National Natural Science Foundation of China (81870207).

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Authors and Affiliations

  1. Department of Critical Care Medicine, Tianjin Medical University General Hospital, Anshan Road No.154, Heping District, Tianjin, 300052, China

    Hao Shen, Keliang Xie & Xiaoye Wang

  2. Department of Cardiovascular Surgery, Tianjin Medical University General Hospital, Anshan Road No.154, Heping District, Tianjin, 300052, China

    Yikui Tian

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  1. Hao Shen
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  2. Keliang Xie
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  3. Yikui Tian
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  4. Xiaoye Wang
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HS, KX and XW wrote the main manuscript text and prepared Figures 1–7. YT help improve the language. All authors reviewed the manuscript.

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Correspondence to Xiaoye Wang.

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Shen, H., Xie, K., Tian, Y. et al. N6-methyladenosine writer METTL3 accelerates the sepsis-induced myocardial injury by regulating m6A-dependent ferroptosis. Apoptosis 28, 514–524 (2023). https://doi.org/10.1007/s10495-022-01808-y

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