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Sanicula europaea L. is a perennial plant that belongs to the family Apiaceae. Traditionally, it has been used for wound healing and upper respiratory tract disorders. Saponin glycosides, as major constituents, are responsible for anti-inflammatory and antiproliferation activities that may have benefits in PAH.1 2Pulmonary arterial hypertension (PAH) is a damaging cardiovascular disease characterized by the narrowing of the small pulmonary blood vessels leading to right heart failure and pre-mature death. The treatment of PAH is limited and aimed to improve symptoms and hence there is an urgent need for new drugs. We hypothesized that as the competing processes of bone morphogenetic protein (BMP) and transforming growth factor-β (TGF-β) pathways are tightly regulated in PAH, agents that restore the balance between these two pathways may provide therapeutic intervention.3–5Materials and Methods S. europaea herb was extracted with 70% methanol and the concentrated extract partitioned with ethyl acetate and then with butanol. The dried butanol fraction was dissolved in methanol and dropped into diethyl ether to give crude glycosides which were separated on a Sephadex LH20, followed by Preparative-HPLC using a reversed-phase C-18 silica column. Pure saponin glycosides (G2 and G4) were isolated as major constituents. Biological evaluation of these glycosides on cell proliferation using the MTT assay and on BMP and TGFβ pathways was carried out using reporter assays and western blots.Results and Discussion The butanol fraction of S. europaea is rich with saponin glycosides. Six glycosides were isolated including G2 and G4 as the major components which differ in their substitution and sugar moieties. Their antiproliferative activities were investigated on mutant mouse pulmonary arterial smooth muscle cells (mPASMCs) harbouring a pathogenic bmpr2 mutation (pR899X), where G2 and G4 showed a differential inhibitory effect on cell growth (IC50=2.24 ± 0.08 µM and IC50=8.58 ±0.79 µM, respectively). On the level of protein, phosphorylation of SMAD1/5 protein was promoted by G4 at both concentrations (10 and 1µM) but was inhibited by G2 at 10 µM. Both compounds (G2 and G4) inhibited TGF-β responsive reporter activity at 10µM whilst no effect was seen at 1µM.Conclusions Saponin glycosides G2 and G4 isolated from S. europaeaL. were found to inhibit the proliferation of mPASMC’s as well as TGF-β signalling but BMP signalling was promoted, suggesting that further investigation of these compounds in PAH may be worthwhile.Acknowledgements MIE is grateful to the Ministry of Higher Education of the Arab Republic of Egypt for funding this study.References Arda N, Gören N, Kuru A, et al. Saniculoside N from Sanicula europaeaL. J Nat Prod. 1997;83(97):1170–3.Kowalczyk M, Masullo M, Thiem B, Piacente S, Stochmal A, Oleszek W. Three new triterpene saponins from roots of Eryngium planum. Nat. Prod. Res. 2014;28(9):653–660Sharmin N, Nganwuchu CC, Nasim MT. Targeting the TGF-β signaling pathway for resolution of pulmonary arterial hypertension. Trends Pharmacol. Sci. 2021;42:510–513Osei-Wusuansa M, Mohammed N, Makanjuola D, Habas K, Sener SO, Assi KH, Nasim R, Nawaz S, Gopalan RC, Wright CW, & Nasim MT. Therapeutic resolution of pulmonary arterial hypertension (PAH) using natural products. Targets, 2024;2(4):428–445.Sener SO, Nasim R, & Nasim T. The prospect and challenges of repurposing established drugs in pulmonary arterial hypertension. BioChem, 2024;4(3):236–201.