Unveiling key regulators in the vitamin D receptor signaling pathway: a network-based approach to identify potential therapeutic targets

BACKGROUND: Vitamin D influences cellular functions through vitamin D receptor (VDR)-mediated signaling pathways. Beyond its established role in calcium and phosphorus homeostasis, it plays a vital role in immune responses, cell proliferation, and cardiovascular health. Numerous studies have associated vitamin D deficiency with various clinical conditions; however, a systems biology approach to pinpoint key genes involved in VDR signaling and related clinical phenotypes remains unexplored. Biological networks are complex with several hubs and functional modules that spread among intertwined layers, therefore identifying crucial genes can often be challenging but offer deep insight of disease pathogenesis and theragnostic. METHODS: A network theory approach was employed to identify crucial genes in terms of modularity. This process involved constructing a protein-protein interaction (PPI) network of genes associated with the VDR signaling pathway, followed by modular analysis and topological scoring using metrics such as degree distribution, clustering coefficient, and neighborhood connectivity. Using this approach, 5 (BMP2, TNFSF11, IRS1, SLC2A1, and PDGFRB) Motif Hubs (MHs) were identified as key regulators, which were deeply embedded from top to bottom throughout the network, influenced the network down to the motif level. RESULTS: The identified five key regulators played a central role in the highly clustered module 2 and were essential for the stability of the entire network, indicating quick accessibility to the molecules and rapid information processing. Functional analysis of the top five modules displayed their strong correlation with enzyme binding, signaling receptor binding, and ligand activity. Similarly, disease association analysis also predicted their relationship with neoplasms, nervous system disorders, and immune system disorders. CONCLUSIONS: The current findings warrant experimental biochemical validation of the observed key regulators, which may offer potential therapeutic targets for treating cardiovascular diseases, cancer, diabetes, and neurological disorders associated with vitamin D deficiency.