Ying Wang,1 Yuhang Fan,2 Mengjiao Li,2 Zheming Song,2 Pengcheng Wang,3 Fei Xie,4 Yuqi Miao,2 Yifan Wang,5 Peng Zhang,5,* Qiang Zhan6,* 

1Department of Pharmacy, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang, People’s Republic of China; 2The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Tuberculosis, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang, People’s Republic of China; 4Department of Otolaryngology, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang, People’s Republic of China; 5Department of Orthopedic, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang, People’s Republic of China; 6Department of Massage, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Qiang Zhan, Department of Massage, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang, People’s Republic of China, Email zqtow@163.com Peng Zhang, Department of Orthopedic, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang, People’s Republic of China, Email zhangpbs2017@163.com

Background: Steroid-related osteonecrosis of the femoral head (SONFH) is bone death resulting from the use of chronic glucocorticoids. Due to its high incidence and lack of effective treatment, which is still a challenging problem in orthopedic surgery. Cornus officinalis (SZY) is usually used as a traditional use for the treatment of SONFH and plays a major role in traditional prescriptions, however, the specific pharmacological mechanisms of action remain unclear. This study is to investigate the mechanisms of SZY against SONFH via network pharmacology and experimental validation analysis.
Methods: The active components and related targets of SZY and related-SONFH targets were collected from public databases. The protein–protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed to predict the core targets and pathways of SZY in the treatment of SONFH. Then, AutoDock Vina was used for molecular docking verification. Finally, the reliability of the network pharmacology prediction results was verified through a mice SONFH model in vivo experiment.
Results: Through the identification of common targets between the active components of SZY and targets related to SONFH, a total of 66 shared targets were identified. The topological analysis of the PPI network identified nine key targets. GO and KEGG enrichment analyses showed that SZY treatment for SONFH mainly include apoptosis and IL-17 signaling pathways. Molecular docking and molecular dynamics simulations results indicated that the active components in SZY exhibited high affinity for these targets. Animal experiments demonstrated that SZY reduced femoral head damage in SONFH mice, significantly downregulating TNF (p< 0.01) and IL-6 (p< 0.05) and modulating Bcl-2/Caspase-3 expression.
Conclusion: Our study provides preclinical evidence that SZY alleviates SONFH by suppressing inflammation and apoptosis, supporting its traditional use and informing further translational research.

Keywords: steroid-related osteonecrosis of the femoral head, cornus officinalis, network pharmacology, molecular mechanisms, apoptosis, inflammation