Tanshinone IIA as a therapy for PCOS via FOS/JUN/TP53 axis: Evidence from network pharmacology of Bajitian-Danshen pair

Abstract

Polycystic ovary syndrome (PCOS) is a common disease affecting women of reproductive age; there is a need for interventions to address this condition. Herein, the network pharmacology approach was used to explore the potential of combining Morindae Officinalis Radix (Bajitian) and Radix Salviae (Danshen) for treating PCOS. The bioactive ingredients of the Bajitian-Danshen pair were identified and used for predicting potential therapeutic target genes. Genes related to PCOS were predicted by keyword search from various databases and intersected with the predicted targets of the active components of the Bajitian-Danshen pair to obtain key target genes, which were used for building the “active compound-target gene” pharmacological network. The TCGAbiolinks package in the R environment was used for functional enrichment analysis. In addition, in vivo and in vitro PCOS models were established to explore the effect of the key bioactive compound on the treatment of PCOS and the underlying mechanisms. Histopathological analysis was performed by hematoxylin and eosin staining, while the detection of hormone and cytokine levels was performed by conducting ELISA. Immunofluorescence and western blotting were used for protein expression analysis. Tanshinone IIA (Tan-IIA) was found to be the ingredient with the highest number of target genes. The protein–protein interaction (PPI) network analysis revealed that JUN, FOS, TP53, PTGS2, MMP9, CDKN1A, BCL2, DPP4, and CASP3 were key target genes of Tan-IIA in PCOS. The docking analysis showed the interaction of Tan-IIA with FOS. Thus, the therapeutic potential of Tan-IIA in PCOS and its effect on FOS were evaluated experimentally. A rat model of PCOS was established and subsequently treated with Tan-IIA. Tan-IIA treatment attenuated the deleterious effects associated with PCOS and downregulated TP53, FOS and JUN mRNA and protein expression levels in the ovarian tissue of PCOS rats. In addition, the activation of FOS expression was followed by the exacerbation of the deleterious effect of PCOS and increased expression levels of JUN and TP53. Thus, we concluded that the Bajitian-Danshen pair, especially the Tan-IIA ingredient, counteracts PCOS‑induced damage by possibly regulating the FOS/JUN/TP53 axis.

Keywords

• Network pharmacology
• Tanshinone IIA
• Polycystic ovary syndrome
• TP53
• FOS
• JUN