Herb-derived compounds from Radix Salviae decoction (RSD) modulated cell death of vascular smooth muscle cells

• Abnormal smooth muscle cell death is critical for cardiovascular disease progression. • This study explored the effects of Radix Salviae decoction in modulating cell death. • Network pharmacology and experiments identified related key targets and pathways. • It revealed that compounds promoted pyroptosis, inhibit autophagy and apoptosis. • The study suggests potential therapeutic implications for cardiovascular diseases. Prior research has suggested that herb-derived compounds from Radix Salviae decoction (RSD) may have anti-inflammatory, antioxidant, antithrombotic and cardiac function improvement properties in cardiovascular system diseases. However, the efficacy and mechanism of herb-derived compounds from RSD for modulating cell death of vascular smooth muscle cells (VSMC) have yet to be investigated. This study aimed to investigate the effects of RSD in modulating cell death of vascular smooth muscle cells and elucidate the underlying mechanisms. Chemical constituents were analyzed through literature and databases. Network pharmacological analysis identified targets for herb-derived compounds from RSD and cell death. A protein-protein interaction network was constructed using String, followed by GO and KEGG analyses to explore pathways affecting vascular smooth muscle cell death. Network pharmacological analysis identified the targets for the three compounds from RSD (Tanshinone ⅡA (DST), Santalol (TXC), and Bornyl ester (LNZ)) and three kinds of cell death (pyroptosis, autophagy and apoptosis). Large nodes such as CASP8, CASP3, TP53, JUN and BAX were observed at the center of the targets network, suggesting that they play key roles in protein interaction networks. In serum-free medium (SFM) conditions of VSMC in vitro , treatment with the herb–derived compounds from RSD significantly promoted pyroptosis of VSMC indicated by increased mRNA levels of GSDMD and GSDME, and the increased mRNA levels of IL-1β. These compounds also inhibited autophagy, as they reduced the expression of ATG12, and decreased the LC3-II/I ratio in VSMC; and the compounds decreased the proportion of early apoptotic cells indicated by flow cytometry. Furthermore, cytokines of IL-6 and TNF-α were notably inhibited after treatment with these compounds. For the related cell signaling transduction, the herb-derived compounds from RSD suppressed PI3K-AKT while activating the NF-κB signaling pathway. This study reveals that treatment of nutrition-depleted VSMC with DST, TXC, and LNZ leads to the promotion of pyroptosis and downregulation of inflammatory factor expression, alongside reduction of autophagy and early apoptotic cells.