Journal Article

Bilobalide attenuates steroid-induced osteonecrosis of the femoral head by upregulating the ERK/HIF-1α signaling pathway and promoting angiogenesis-osteogenesis coupling

Xu, Hanbo, Chen, Qi, Zhang, Kun, Wang, Bo, Liang, Hu, Hao, Yangquan

2026

Overview

Steroid-induced osteonecrosis of the femoral head (SONFH) is a severe bone disease associated with long-term glucocorticoid use, characterized by impaired bone metabolism and vascular insufficiency. Bilobalide (BB), a natural sesquiterpene from Ginkgo biloba, exhibits anti-apoptotic, antioxidant, and pro-angiogenic properties, yet its role in SONFH remains unclear. We integrated network pharmacology and molecular docking to predict the targets and pathways of BB in SONFH. Key targets were validated using molecular docking software. For in vivo experiments, a rat SONFH model was established using methylprednisolone (MPS), and BB was administered orally. Micro-CT, H&E staining, TUNEL assay, and immunohistochemistry were employed to evaluate bone microstructure, apoptosis, and the expression of osteogenic and angiogenic markers. Immunofluorescence was used to assess HIF-1α expression in rat femoral head tissues. For in vitro experiments, MC3T3-E1 osteoblasts were treated with dexamethasone(DEX) and BB. Cell viability was detected using the CCK-8 assay, and the protein levels of the HIF-1α and ERK pathways were examined by Western blot. Network pharmacology identified 94 common targets between BB and SONFH, with enrichment in HIF-1 and ERK signaling pathways. Molecular docking confirmed strong binding affinities between BB and core targets. In MPS-induced rats, BB treatment significantly improved bone mineral density, trabecular microstructure, and reduced osteocyte apoptosis. BB also upregulated HIF-1α, Runx2, OCN, CD31, and VEGF expression, indicating enhanced osteogenesis and angiogenesis. In vitro, BB rescued dexamethasone-induced suppression of osteoblast viability and upregulated the ERK/HIF-1α pathway. Bilobalide attenuates SONFH progression by activating the ERK/HIF-1α signaling pathway, promoting osteogenesis and angiogenesis, and reducing osteocyte apoptosis. These findings highlight BB as a promising candidate for SONFH prevention and support the utility of network pharmacology in mechanistic natural product research.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/154 / 631/80 / 692/308 / 692/699 / Angiogenesis / Animals / Apoptosis / Apoptosis - drug effects / Bilobalide / Bone density / Bone diseases / Bone mineral density / Bone turnover / Cancellous bone / Cbfa-1 protein / Cell viability / Cholecystokinin / Computed tomography / Cyclopentanes - pharmacology / Dexamethasone / Dexamethasone - adverse effects / Disease / Disease Models, Animal / Drug dosages / Femur / Femur Head - drug effects / Femur Head - metabolism / Femur Head - pathology / Femur Head Necrosis - chemically induced / Femur Head Necrosis - drug therapy / Femur Head Necrosis - metabolism / Femur Head Necrosis - pathology / Furans / Genes / Ginkgolides - pharmacology / HIF-1α / Humanities and Social Sciences / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Hypoxia-inducible factor 1a / Immunofluorescence / Immunohistochemistry / Intervention / Laboratory animals / Male / MAP Kinase Signaling System - drug effects / Metabolism / Methylprednisolone / Methylprednisolone - adverse effects / Mice / Molecular docking / Molecular Docking Simulation / multidisciplinary / Natural products / Necrosis / Neovascularization, Physiologic - drug effects / Network pharmacology / Oral administration / Osteoblasts / Osteoblasts - drug effects / Osteoblasts - metabolism / Osteogenesis / Osteogenesis - drug effects / Osteonecrosis / Pharmacology / Proteins / Rats / Rats, Sprague-Dawley / Respiration / Science / Science (multidisciplinary) / Signal transduction / Signal Transduction - drug effects / Software / SONFH / Steroids / Up-Regulation - drug effects / Vascular endothelial growth factor