DNMT1-mediated CRNDE hypermethylation aggravates abdominal aortic aneurysm by promoting ferroptosis through the CRNDE-FUS-apelin axis.

This study aimed to investigate the role and molecular mechanism of Long non-coding RNAs (lncRNAs) colorectal neoplasia differentially expressed (CRNDE) in angiotensin II (Ang II)-induced ferroptosis of vascular smooth muscle cells and the formation of abdominal aortic aneurysm (AAA). An in vitro AAA model was established by stimulating human aortic vascular smooth muscle cells (HAVSMCs) with Ang II, and an in vivo AAA model was generated by Ang II infusion in ApoE-/- mice. The results showed that Ang II significantly downregulated CRNDE expression. CRNDE overexpression inhibited ferroptosis, improved cell viability, and reduced apoptosis. Mechanistic studies revealed that Ang II suppressed CRNDE expression through DNA methyltransferase 1 (DNMT1)-mediated promoter hypermethylation. CRNDE directly bound to fused in sarcoma (FUS) protein via the GGUG motif within its 61-120 nt region, forming a CRNDE-FUS-apelin promoter ternary complex that upregulated apelin expression by enhancing promoter activity at the transcriptional level and increasing mRNA stability at the post-transcriptional level. Functional rescue experiments confirmed that CRNDE upregulated apelin in a FUS-dependent manner to inhibit ferroptosis. In vivo experiments further demonstrated that CRNDE overexpression significantly suppressed Ang II-induced AAA formation. In conclusion, CRNDE inhibits vascular smooth muscle cell ferroptosis and AAA progression through the formation of the CRNDE-FUS-apelin axis, and targeting this signaling axis may represent a potential therapeutic strategy for AAA.