Through the “disease-gene-target-drug” interaction network, network pharmacology integrates disciplines such as systems biology and bioinformatics, offering a novel approach to study the mechanisms of drug active components. By systemically analyzing a drug’s intervention and impact on disease networks, it reveals potential drug mechanisms at the molecular level, such as active ingredients and protein targets. This approach enables efficient exploration of traditional medicines in terms of their multi-component, multi-target, and multi-pathway mechanisms. Traditional Chinese medicine has indeed demonstrated considerable promise in the prophylaxis and therapeutic intervention of ONFH. Concurrently, the underlying mechanisms of traditional Chinese medicine in addressing osteonecrosis of the femoral head are increasingly gaining traction among the scientific community.[21].
The findings from the investigation intimate that epimedium could exert its effects on the pathogenesis of SONFH via a multi-pronged strategy, encompassing numerous components, targets, and pathways. The five core genes of Epimedium in the treatment of SONFH were KCNH2, BCL2L1, E2F2, PTGS2 and ABCG2. The protein produced by BCL2L1 is associated with the BCL-2 protein family. Members of the BCL-2 family act as regulators that promote or inhibit apoptosis. These regulators play pivotal roles in a multitude of cellular processes. The proteins encoded by BCL2L1 are situated on the outer mitochondrial membrane and have been found to modulate the opening of the outer mitochondrial membrane channel (VDAC). Both these factors are powerful triggers for cell apoptosis. A study conducted by Komori et al reveals that overexpression of BCL2L1 in osteoblasts leads to a significant augmentation in both trabecular and cortical bone volumes, maintaining their structural integrity. This effect is primarily attributed to the prevention of osteoblast apoptosis, especially in osteoporosis scenarios[22]. The enzyme prostaglandin-endoperoxide synthase (PTGS), commonly referred to as cyclooxygenase, is pivotal in prostaglandin biosynthesis. This enzyme is versatile, functioning both as a dioxygenase and a peroxidase. PTGS exists in two isozymic forms: the constitutive PTGS1 and the inducible PTGS2. Their distinction lies in the patterns of their expression and their distribution across tissues. Governed by specific induction paradigms, it is posited to be integral for the prostanoid synthesis implicated in inflammation and cellular proliferation. A work by Qingyu Zhang underscored PTGS2 as a pivotal biomarker for glucocorticoid-induced osteonecrosis of the femoral head, heralding it as an auspicious target for tissue regeneration and SONFH therapy. PTGS2’s sosteogenic implications on BMSCs were scrupulously evaluated in in vitro studies.[23]. The protein encoded by the E2F2 is a member of the E2F family of transcription factors. This collective is instrumental in the meticulous regulation of the cell cycle, the functionalities of tumor-suppressive entities, and is also a prime target for the transformative proteins stemming from small DNA tumor viruses. A study on MiR-125a-5p-rich exosomes, sourced from mesenchymal stem cells, revealed their potential in thwarting chondrocyte degeneration by specifically targeting E2F2 in traumatic osteoarthritis contexts[24].
In a pathway enrichment analysis, Epimedium emerged as a salient player in the therapeutic approach to SONFH, exerting its influence predominantly through pathways related to apoptosis, immune responses, inflammation, cellular stress, and oncogenesis. A comprehensive enrichment assessment of the 5 targets gene was conducted using the GeneMANIA database. Biological processes are mainly manifested in intrinsic apoptotic signaling pathway, export across plasma membrane and epithelial cell apoptotic. Cellular component is mainly manifested in organelle outer membrane, outer membrane, nuclear membrane, membrane raft, and membrane microdomain. The molecular function is mainly manifested in death domain binding, ABC − type xenobiotic transporter activity, efflux transmembrane transporter activity, and inward rectifier potassium channel activity. KEGG signaling pathway was mainly enriched in small cell lung cancer, Pancreatic cancer, Chronic myeloid leukemia and NF − kappa B signaling pathway.
Moreover, certain limitations in this study warrant mention. Initially, owing to the constraints of our screening parameters, only the predominant targets of Epimedium were subject to analysis, circumscribing the scope of our findings to an extent. Additionally, while network pharmacology and bioinformatics tools allow for an expansive delineation of targets and pathways, empirical corroboration through both in vitro and in vivo investigations remains imperative. This will elucidate the precise molecular modus operandi of Epimedium in addressing osteonecrosis of the femoral head, thereby catalyzing the modernization of traditional Chinese medicinal practices.