ROS-activated CD147-type I interferon signaling axis drives vascular smooth muscle cell fate transition and abdominal...

The transition of healthy contractile vascular smooth muscle cells to an inflammatory and senescent phenotype is a key driver of abdominal aortic aneurysm (AAA). Although CD147 is highly expressed in VSMCs and upregulated in aneurysmal tissue, the precise role of VSMC-derived CD147 in phenotypic switching and AAA pathogenesis remains elusive. Here, we identified a previously unrecognized nuclear localization of CD147 in VSMCs, and pathological stimuli upregulated the nuclear CD147 expression through reactive oxygen species-dependent mechanisms. Multi-omics analysis integrating RNA sequencing, CUT&Tag, and protein interactome profiling revealed that nuclear CD147 directly interacts with the STAT1/STAT2 complex to activate the IRF7-IFNα/β axis under oxidative stress (H₂O₂ exposure), thereby driving VSMC senescence and inflammatory reprogramming. Functionally, CD147 deletion in VSMCs significantly mitigated Angiotensin II- and CaPO₄-induced AAA formation, accompanied by improved VSMC phenotype, reduced vascular inflammation and extracellular matrix degradation in vivo. Pharmacological inhibition of CD147 using Myricetin, a food-derived natural small-molecule compound, effectively discouraged oxidative stress-induced VSMC fate transition in vitro, and suppressed AAA progression and improved vascular integrity in two murine AAA models, underscoring its therapeutic potential. Collectively, these findings identify CD147 as a key driver of interferon-mediated VSMC fate transition, providing mechanistic insights into AAA progression and a promising therapeutic target for vascular diseases.