Exploring the therapeutic potential of 18β-Glycyrrhetinic acid in pulmonary arterial hypertension by integrating network pharmacology and experimental validation

Pulmonary arterial hypertension (PAH) is characterized by elevated pressure in the pulmonary arteries and can result in right heart failure and possible death.18β-Glycyrrhetinic acid (18β-GA), a beneficial substance found in licorice, shows great potential for medicinal use. Through network pharmacology and experimental validation, this study examined the probable mechanism of 18β-GA in treating PAH. The analysis of the potential pharmacological activities of 18β-GA was conducted using the network pharmacology method. The network of interactions between proteins was created by identifying shared targets of 18β-GA and PAH across multiple databases. Pathway enrichment was then conducted to determine the key targets. Validation of the interactions between 18β-GA and key targets was performed by molecular docking. Ultimately, we confirmed the modes of operation by utilizing a monocrotaline (MCT)--induced PAH model in rats. A total of 197 potential targets for 18β-GA and 1713 potential targets associated with PAH were successfully identified. Of these, 79 targets were identified as common to both 18β-GA and PAH. Through the analysis of the PPI network, identified key targets, including IL6, AKT1, ALB, BCL2, NFKB1, IL1B, SRC, MMP9, PPARG, MAPK3, PTGS2, ESR1, TNF, CTNNB1 and CASP3. Furthermore, the analysis of molecular docking indicated that SRC exhibited the highest affinity for 18β-GA. The efficacy of 18β-GA in mitigating the advancement of MCT-induced PAH in rats was proven by in vivo investigations. This study presents initial findings about the molecular mechanism by which 18β-GA exerts its therapeutic effects on PAH. The findings suggest that using 18β-GA for treating PAH may involve the deactivation of SRC and the reduction of oxidative stress. [Display omitted] •18β-Glycyrrhetinic acid (18β-GA), a compound found in licorice, shows promising medicinal potential for the treatment of PAH.•Network pharmacology analysis revealed 197 potential targets for 18β-GA and 1713 targets related to PAH, with 79 overlapping targets.•Key targets identified through pathway enrichment and molecular docking include IL6, AKT1, ALB, BCL2, NFKB1, IL1B, SRC, MMP9, PPARG, MAPK3, PTGS2, ESR1, TNF, CTNNB1, and CASP3.•In vivo experiments with a rat model of PAH induced by monocrotaline confirmed the efficacy of 18β-GA in attenuating disease progression.•Mechanistic analysis suggests that the therapeutic benefit of 18β-GA on PAH may be due to inactivation of SRC and reduction of oxi