The vitamin D receptor story: discovery, control, and genomic reach.

The vitamin D receptor (VDR) is a ligand-activated nuclear receptor that mediates the biological actions of vitamin D and is a critical regulator of mineral homeostasis, cellular differentiation, immune function, and metabolism. VDR is a high-affinity intracellular binding protein for the most active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25D). Early biochemical and molecular studies established VDR as a member of the nuclear receptor superfamily, functioning as a transcription factor that heterodimerizes with the retinoid X receptor and binds vitamin D response elements to regulate gene expression. Since the cloning of the VDR gene in the 1980s, characterization of its structural domains and identification of coregulators significantly advanced understanding of its genomic mechanisms of action. Over the past several decades, research has expanded the scope of VDR biology beyond classical calcium and phosphate metabolism. Genome-wide binding analyses and transcriptomic studies have revealed extensive VDR cistromes and context-dependent gene networks across diverse tissues. These advances have positioned VDR as a key factor linking vitamin D availability to tissue-specific outcomes. Despite substantial progress, fundamental questions remain, including mechanisms governing tissue-specific VDR actions, integration of genomic signaling pathways, and the role of VDR in complex diseases, such as cancer, autoimmune disorders, and aging. In addition, how VDR function is modulated by chromatin context, metabolic state, and the microbiome remains incompletely understood. Here, we summarize what is known about these actions of VDR and its history of discovery. Addressing these questions will be essential for translating mechanistic insights into improved therapeutic strategies targeting the vitamin D axis.