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

Area of Science:

• Biomedical Science
• Molecular Biology
• Cardiovascular Research

Background:

• Cerebrovascular diseases, including atherosclerosis, cause high mortality and disability globally.
• Endothelial cell injury is a primary driver of atherosclerosis, the main cause of cerebrovascular disease.
• Ferroptosis, a form of programmed cell death involving iron and lipid peroxidation, is implicated in atherosclerosis progression.

Purpose of the Study:

• To investigate the role and mechanism of YTHDF2 in vascular endothelial cells during atherosclerosis.
• To elucidate how YTHDF2 influences endothelial cell proliferation and ferroptosis in the context of atherosclerosis.

Main Methods:

• Utilized human umbilical vein endothelial cells (HUVECs) treated with oxidized low-density lipoprotein (ox-LDL).
• Performed gain-of-function and loss-of-function assays to assess YTHDF2's impact on cell proliferation and ferroptosis.
• Employed in silico analysis to identify potential m6A modification sites on SLC7A11 mRNA and YTHDF2 binding interactions.

Main Results:

• YTHDF2 expression was upregulated in ox-LDL treated HUVECs.
• Overexpression of YTHDF2 inhibited HUVEC proliferation and promoted ferroptosis.
• Silencing YTHDF2 enhanced HUVEC proliferation and reduced ferroptosis.
• YTHDF2 binds to SLC7A11 mRNA in an m6A-dependent manner, promoting its degradation and reducing stability.

Conclusions:

• YTHDF2 accelerates ferroptosis in endothelial cells, contributing to cerebrovascular atherosclerosis.
• The findings provide insights into the pathological mechanisms of cerebrovascular disease.
• Targeting YTHDF2 may offer a therapeutic strategy for atherosclerosis.