A predictive insight into the ATRNL1-mediated ceRNA network driving abdominal aortic aneurysm progression via VSMC phenotypic switching.

OBJECTIVE

Current therapeutic options for abdominal aortic aneurysm (AAA) are primarily invasive and carry significant risks, highlighting an urgent need for non-invasive pharmacological strategies. This study aimed to identify a novel ceRNA axis driving AAA progression and to explore potential therapeutic agents through systematic drug repositioning.

METHODS

Transcriptomic data from human AAA (GSE183464) and a vascular smooth muscle cell (VSMC) phenotypic switching dataset (GSE77278) were integrated. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were employed to identify an ATRNL1-centered ceRNA axis. Mechanistic interactions were validated through histological and immunofluorescence analyses. Systematic screening of the DSigDB database identified drug repositioning candidates, followed by network pharmacology analysis. The predicted targets and mechanisms were further validated via wet-lab experiments in both primary human and mouse VSMCs.

RESULTS

Analysis revealed a significant downregulation of the ATRNL1/hsa_circ_0020097 axis in both AAA tissues and phenotypically modulated VSMCs. Mechanistically, hsa_circ_0020097 functions as a molecular sponge for hsa-miR-3185, and its downregulation enhances miR-3185-mediated repression of the key target gene LPP. Histopathological examination confirmed classic AAA hallmarks, including elastic lamina degradation and medial thickening, accompanied by a marked reduction in the co-localization of LPP and the VSMC marker α-SMA, which correlated with disease severity. Notably, qPCR validation in primary human aortic VSMCs (HAVSMCs) and mouse VSMCs confirmed that the entire ATRNL1/hsa_circ_0020097/miR-3185/LPP axis exhibits synchronized expression fluctuations under AAA-related stress. Drug repositioning identified Bazedoxifene as the top candidate. In vitro experiments demonstrated that Bazedoxifene significantly restores the expression of this ceRNA axis in both human and mouse cells, with optimal effects observed at 10 μM.

CONCLUSION

This study elucidates a novel ATRNL1/hsa_circ_0020097/miR-3185/LPP ceRNA axis that promotes AAA development by driving VSMC phenotypic switching. Our findings suggest that Bazedoxifene exerts protective effects by targeting the ATRNL1 axis to modulate VSMC phenotypes. This work not only uncovers a previously unrecognized pathogenic axis in AAA but also provides a directly translatable pharmacological strategy for its clinical management.