Paeoniflorigenone inhibits the progression of cholangiocarcinoma via HIF1A and enhances the chemotherapy sensitivity of cisplatin.

Cholangiocarcinoma (CCA) is a type of malignant tumor that originates from the bile duct epithelium and has relatively few treatment options. Paeoniflorigenone (PFG) extracted from Moutan cortex has the effect of selectively inducing tumor cell apoptosis and anti-tumor proliferation. However, its role in CCA remains unclear. Firstly, the core targets and molecular mechanisms of PFG in treating CCA were screened through network pharmacology. Subsequently, the proliferation inhibition and apoptosis induction effects of PFG acting on CCA cells were initially explored by CCK8 assay, colony formation assay, cell apoptosis, and western blot assay, while the HIF1A signaling pathway was verified by recovery experiment. Finally, the synergistic effect of PFG and cisplatin on CCA was explored in vivo. Based on network pharmacology, 20 target genes were obtained and HIF1A was the core target of PFG in treating CCA. Molecular docking and molecular dynamics simulation of PFG and HIF1A were stable, and the binding energy was - 16.9 kcal/mol. In terms of molecular mechanism, PFG could significantly inhibit proliferation and colony formation, and induce more apoptosis in RBE cells and HUCCT1 cells via HIF1A, which was verified by the recovery experiment. Furthermore, the combination of PFG and cisplatin could enhance the proliferation inhibition and apoptosis promotion of CCA in vitro and in vivo while further reducing the protein expression of HIF1A. PFG could inhibit proliferation and induce apoptosis in CCA via HIF1A. Moreover, PFG combined with cisplatin could enhance the therapeutic effect in CCA.