ABSTRACT Background : Thoracic aortic dissection (TAD) is a lethal vascular emergency lacking targeted therapies. Fibroblast activation protein (FAP), a protease implicated in tissue remodeling, exhibits unknown roles in TAD pathogenesis. Methods : Human TAD specimens and β‐aminopropionitrile‐induced TAD models were used to assess FAP expression. Global and fibroblast‐specific Fap knockout mice were generated to evaluate biological effects of FAP. Bulk and single‐cell RNA sequencing were used to map cellular crosstalk and dysregulated signaling pathways. A combination of pharmacological inhibition (Ac‐Gly‐BoroPro), surface plasmon resonance (SPR), co‐immunoprecipitation (co‐IP), and functional rescue experiments was utilized to dissect the enzymatic versus nonenzymatic functions of FAP and its interaction with PLAUR/ITGB1 signaling. Results : Fibroblast‐derived FAP was significantly upregulated in TAD lesions. Fap deletion markedly attenuated inflammatory infiltration, extracellular matrix degradation, and TAD incidence. Surprisingly, pharmacological inhibition of FAP's enzymatic activity failed to protect against TAD. SPR, co‐IP, and functional assays revealed that FAP binds directly to macrophage PLAUR via nonenzymatic sites. This interaction triggers ITGB1/FAK signaling, promoting a pro‐inflammatory macrophage phenotype that drives TAD progression. Conclusion : This study demonstrates that FAP promotes TAD through a nonenzymatic mechanism involving fibroblast‐macrophage crosstalk via the FAP/PLAUR/ITGB1/FAK axis. Targeting this pathway might offer a promising therapeutic strategy for TAD.
Zhu et al. (2026) studied this question.