Background and aims: Cellular senescence and inflammation-mediated phenotypic switch in smooth muscle cell (SMC) are pivotal factors in the aortic degenerative remodeling and the development of aortic dissection. Chlorogenic acid (CGA), a natural polyphenolic compound of plant origin, exhibits remarkable anti-aging and anti-inflammation properties. However, the role of CGA in the aortic degenerative remodeling and aortic dissection remains elusive.

Methods: In this study, a BAPN (beta-aminopropionitrile)-induced aortic dissection model in vivo and DOX (doxorubicin)-induced cell senescence model in vitro were employed, in combination with activity-based protein profiling (ABPP) technology, to explore the mechanism by which CGA inhibits aortic dissection.

Results: The results revealed that CGA could prophylactically and therapeutically prevent BAPN-induced aortic dissection in mice, with reduced mice death and aortic diameter, inhibited aortic SMC senescence, inflammatory responses and phenotypic switch. Transcriptome sequencing of aortic tissues demonstrated that CGA treatment downregulated the expression of genes related to senescence and SMC synthesis, while upregulating the expression of contractile genes in aortic SMCs. These findings were further validated in DOX-induced senescent SMCs. Based on ABPP technology, a CGA chemical probe was utilized to exploring its protein targets, and Mettl3 was identified and verified as a potential target of CGA in senescent SMCs. Inhibition of Mettl3 using a specific inhibitor reduces the senescence and phenotypic transformation of SMCs in vitro. Concomitantly, Mettl3 specific inhibitor could also prophylactically and therapeutically prevent BAPN-induced aortic dissection in mice.

Conclusions: In summary, this study offers novel insights into halting the progression of aortic dissection and may facilitate the application of CGA in the prevention of aortic dissection.