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Wnt5a Functions as a Novel Ferroptosis Inhibitor to Alleviate Aortic Dissection by Enhancing DHODH mRNA Stability
Background: The loss of aortic smooth muscle cells (ASMCs) caused by programmed cell death (PCD) is considered to be a crucial pathogenesis of aortic dissection (AD). Nowadays, ferroptosis has been widely studied as a novel type of PCD, yet whether N6-methyladenosine (m6A) methylation can influence AD pathogenesis by modulating ferroptosis is not known.
Methods: The influence of Wnt5a, ALKBH5, or DHODH on ASMCs ferroptosis was assessed by cell viability assay and intracellular Fe2+ as well as lipid peroxidation detection. We predicted the upstream and downstream regulatory molecules of ALKBH5 through sequencing of clinical samples in combination with bioinformatics analysis, and then screened and validated them. Relevant regulatory mechanisms were investigated by RIP, MeRIP, ChIP, TOPFlash, dual-luciferase reporter, and ubiquitination assays. BAPN-induced AD mouse model was established in vivo experiments.
Findings: Wnt5a inhibited ferroptosis of ASMCs and alleviated AD progression in vitro and in vivo. Mechanistically, Wnt5a downregulated β-catenin/TCF3 signal via promoting ubiquitination-dependent degradation of β-catenin mediated by SIAH2, thereby suppressing ALKBH5 transcription. The downregulation of ALKBH5 enhances the stability of DHODH mRNA in an m6A-YTHDF1-dependent manner.
Interpretation: Our findings reveal that Wnt5a functions as a novel ferroptosis inhibitor to alleviate AD via enhancing DHODH mRNA stability. These findings provide a novel perspective that targeting ferroptosis or WNT signaling pathway may be a promising strategy for AD treatment.
Funding: This work was supported by grants from the Research Funds by the Department of Finance of Hubei Province (No. SCZ202201) and National Natural Science Foundation of China (No. 82070481).
Declaration of Interest: The authors declare that they have no potential conflicts of interest.
Ethical Approval: The approval of Ethical Committee of the Renmin Hospital of Wuhan University for animal experiments in this study was acquired (WDRM20201107).
Wang, Peng and Wu, Qi and Zou, Wenbin and Shi, Feng and Zhou, Lin and Liang, Jun and Kuang, Linwu and Wang, Zhiwei and Fu, Xiangning, Wnt5a Functions as a Novel Ferroptosis Inhibitor to Alleviate Aortic Dissection by Enhancing DHODH mRNA Stability. Available at SSRN: https://ssrn.com/abstract=4978408 or http://dx.doi.org/10.2139/ssrn.4978408
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