Mechanism of Shuangshen Xionglian Granule in Attenuating EndMT in Atherosclerosis via the FGFR1-TGF-β/Smad2 Axis.

Shuangshen Xionglian Granule (SSXL), a multi-herb traditional Chinese medicine used for atherosclerosis (AS), was investigated for its anti-atherosclerotic effects and its role in modulating endothelial-to-mesenchymal transition (EndMT). In high-fat diet-fed ApoE-/- mice, SSXL ameliorated dyslipidemia, reduced systemic inflammation, and alleviated aortic plaque burden. An integrated approach combining UPLC-QTOF-MS profiling, network pharmacology, and transcriptomics identified 401 SSXL-responsive disease-associated genes, which were enriched in pathways related to TGF-β, MAPK, cAMP, and extracellular matrix organization. In both aortic tissues from these mice and TGF-β2-stimulated human aortic endothelial cells, SSXL preserved endothelial identity and suppressed EndMT. Mechanistically, SSXL restored FGFR1 phosphorylation while concomitantly downregulating TGF-βRI/TGF-β2 expression and Smad2 phosphorylation. Pharmacological inhibition of FGFR1 with PD173074 partially abrogated these protective effects, indicating that SSXL suppresses EndMT, at least in part, through FGFR1-mediated inhibition of the TGF-β/Smad2 signaling axis. These findings suggest that SSXL ameliorates AS through combined lipid-lowering, anti-inflammatory, and anti-EndMT actions, supporting its potential as a multi-target therapeutic candidate for vascular protection in AS.