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Background <p>Atherosclerosis (AS) is a disease marked by lipid metabolism dysfunction. Methylation of 5-methylcytosine (m<sup>5</sup>C) mRNA can regulate AS progression. We investigated the role and mechanism of m<sup>5</sup>C reader ALYREF in AS.</p> Methods <p>ApoE<sup>−/−</sup> mice AS models were constructed. Oil Red O staining evaluated the degree of aortic plaque. Serum LDL and TG levels were assessed. ELISA detected vascular inflammation and ATP production. Expressions of ALYREF, CISD1, and ferroptosis-related proteins were detected by RT-qPCR and Western blot. CCK-8, EdU, and flow cytometry were used to detect cell viability and apoptosis. RIP assay validated the direct binding of ALYREF to CISD1. Mitochondrial morphology was observed by transmission electron microscopy (TEM). Mitochondrial membrane potential was determined by JC-1. Mitochondrial ROS and cytoplasmic ROS were tested by immunofluorescence staining. Oxidative stress damage (MDA), antioxidant enzymes (SOD/GSH), and Fe<sup>2+</sup> levels were detected by kits. Methylated RNA was immunoprecipitated with m<sup>5</sup>C-specific antibody (MeRIP).</p> Results <p>ALYREF expression declined in AS mice and human primary coronary artery endothelial cells (HCAEC) induced by oxidized low-density lipoprotein (ox-LDL). Elevated ALYREF improved ox-LDL-induced HCAEC apoptosis, inflammation, and lipid metabolism. ALYREF elevation attenuated mitochondrial damage and ferroptosis in ox-LDL-exposed HCAEC. ALYREF facilitated the stability and expression of CISD1 mRNA through m<sup>5</sup>C methylation. Reversing CISD1 expression negated the protective effects of ALYREF overexpression against ox-LDL-induced HCAEC damage. ALYREF-mediated epigenetic modification of CISD1 alleviated AS progression by reducing lipid levels and inhibiting ferroptosis in vivo.</p> Conclusion <p>By enhancing m<sup>5</sup>C modification, ALYREF enhances the stability and expression of CISD1 mRNA, which impedes lipid metabolism and endothelial cell ferroptosis in AS and alleviates AS-associated pathological changes.</p> Graphical abstract <p>ALYREF promotes CISD1 mRNA stability by enhancing its m<sup>5</sup>C modification, which increases its expression, thus inhibiting lipid metabolism dysfunction and endothelial cell ferroptosis in AS and improving AS-related pathological alterations.</p>

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ALYREF inhibits ferroptosis in vascular endothelial cells and improves atherosclerosis by epigenetic modification of CISD1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月24日

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  • Jinghai Hua,
  • Ling Yu,
  • Wenjun Xiong,
  • Ru Ying,
  • Qiong Duan,
  • Jianbing Zhu,
  • Xiaoping Peng,
  • Minzi Qiu

摘要

Background

Atherosclerosis (AS) is a disease marked by lipid metabolism dysfunction. Methylation of 5-methylcytosine (m5C) mRNA can regulate AS progression. We investigated the role and mechanism of m5C reader ALYREF in AS.

Methods

ApoE−/− mice AS models were constructed. Oil Red O staining evaluated the degree of aortic plaque. Serum LDL and TG levels were assessed. ELISA detected vascular inflammation and ATP production. Expressions of ALYREF, CISD1, and ferroptosis-related proteins were detected by RT-qPCR and Western blot. CCK-8, EdU, and flow cytometry were used to detect cell viability and apoptosis. RIP assay validated the direct binding of ALYREF to CISD1. Mitochondrial morphology was observed by transmission electron microscopy (TEM). Mitochondrial membrane potential was determined by JC-1. Mitochondrial ROS and cytoplasmic ROS were tested by immunofluorescence staining. Oxidative stress damage (MDA), antioxidant enzymes (SOD/GSH), and Fe2+ levels were detected by kits. Methylated RNA was immunoprecipitated with m5C-specific antibody (MeRIP).

Results

ALYREF expression declined in AS mice and human primary coronary artery endothelial cells (HCAEC) induced by oxidized low-density lipoprotein (ox-LDL). Elevated ALYREF improved ox-LDL-induced HCAEC apoptosis, inflammation, and lipid metabolism. ALYREF elevation attenuated mitochondrial damage and ferroptosis in ox-LDL-exposed HCAEC. ALYREF facilitated the stability and expression of CISD1 mRNA through m5C methylation. Reversing CISD1 expression negated the protective effects of ALYREF overexpression against ox-LDL-induced HCAEC damage. ALYREF-mediated epigenetic modification of CISD1 alleviated AS progression by reducing lipid levels and inhibiting ferroptosis in vivo.

Conclusion

By enhancing m5C modification, ALYREF enhances the stability and expression of CISD1 mRNA, which impedes lipid metabolism and endothelial cell ferroptosis in AS and alleviates AS-associated pathological changes.

Graphical abstract

ALYREF promotes CISD1 mRNA stability by enhancing its m5C modification, which increases its expression, thus inhibiting lipid metabolism dysfunction and endothelial cell ferroptosis in AS and improving AS-related pathological alterations.