Fenbufen suppresses VSMC phenotypic switching and neointimal hyperplasia by targeting HAS2.

Vascular restenosis, driven by intimal hyperplasia and the phenotypic switching of vascular smooth muscle cells, remains a severe complication following interventional surgery. Current clinical strategies yield unsatisfactory outcomes. Fenbufen, a non-steroidal anti-inflammatory drug, has been reported to exert anti-inflammatory effects, but its potential role in vascular restenosis has not yet been elucidated. In vivo experiment, Fenbufen markedly attenuated neointimal formation evaluated by histological staining in a mouse femoral artery wire injury model. Moreover, immunofluorescence staining showed that Fenbufen downregulated the expression of the synthetic marker OPN while upregulating that of the contractile markers α-SMA and CNN1, indicating that Fenbufen inhibits VSMC phenotypic switching. Since Fenbufen is an oral prodrug of Felbinac that exerts anti-inflammatory and analgesic effects through metabolic conversion to Felbinac in vivo, we used Felbinac for our in vitro experiments. In primary human aortic smooth muscle cells (HASMCs), Felbinac significantly attenuated PDGF-BB-induced proliferation, migration, and phenotypic switching. RNA sequencing analysis identified hyaluronan synthase 2 (HAS2) as a critical target of Felbinac. Mechanistic investigations further demonstrated that Felbinac suppressed PDGF-BB-induced proliferation, migration and phenotypic switching of HASMCs via downregulation of HAS2. Besides, Felbinac inhibited the activation of both the PI3K-AKT and MAPK signaling pathways. Finally, Fenbufen alleviated activation of both PI3K-AKT and MAPK pathways in a mouse femoral artery wire injury model. Collectively, these findings demonstrate that Felbinac, the active metabolite of Fenbufen, suppresses VSMC phenotypic switching and neointimal hyperplasia through downregulation of HAS2, thereby identifying HAS2 as a critical therapeutic target for pathological vascular remodeling.