{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:35:03Z","timestamp":1790739303867,"version":"4.1.0"},"reference-count":106,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS","doi-asserted-by":"publisher","award":["KAKENHI #23K15502"],"award-info":[{"award-number":["KAKENHI #23K15502"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Tokiwa Medical Foundation"},{"DOI":"10.13039\/100016976","name":"Fukushima prefecture","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100016976","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Vitamin D signaling via the vitamin D receptor (VDR) regulates calcium\u2013phosphate homeostasis and extensive gene programs controlling cell proliferation, differentiation, immune tone, and metabolism. However, systemic use of the natural agonist 1\u03b1,25-dihydroxyvitamin D3 (calcitriol) for extraskeletal indications is limited by dose-limiting hypercalcemia. This review summarizes VDR biology and the structural basis of ligand action, emphasizing how ligand-induced repositioning of helix 12 and altered coregulator recruitment can be exploited to engineer selective VDR modulators. We highlight medicinal chemistry strategies spanning secosteroidal analogs with side-chain or ring modifications and emerging non-seco scaffolds and discuss clinically established agents (e.g., calcipotriol and paricalcitol) alongside experimental \u201csuper-agonists\u201d, partial agonists, and antagonists designed to widen the therapeutic window. Finally, we discuss current evidence for VDR targeting across cancer, metabolic disease, fibrosis, and immune-inflammatory disorders, including mechanisms of resistance such as dysregulated vitamin D metabolism and epigenetic repression. Structural and epigenomic insights are positioning next-generation VDR ligands as tissue- and pathway-biased therapeutics that may enable safer, mechanism-guided translation beyond bone and mineral indications.<\/jats:p>","DOI":"10.3390\/biom16030396","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T14:43:07Z","timestamp":1772808187000},"page":"396","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Synthetic Modulators of the Vitamin D Receptor: From Structural Innovation to Disease-Specific Applications"],"prefix":"10.3390","volume":"16","author":[{"given":"Tram Thi-Ngoc","family":"Nguyen","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Iryo Sosei University, Iino, Chuo-dai, Iwaki 970-8551, Fukushima, Japan"},{"name":"Research Institute of Innovative Medicine, Tokiwa Foundation, Iwaki 971-8112, Fukushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7932-8724","authenticated-orcid":false,"given":"Tomohiro","family":"Kurokawa","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Iryo Sosei University, Iino, Chuo-dai, Iwaki 970-8551, Fukushima, Japan"},{"name":"Research Institute of Innovative Medicine, Tokiwa Foundation, Iwaki 971-8112, Fukushima, Japan"},{"name":"School of Medicine, Fukushima Medical University, Fukushima 960-1295, Fukushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Kanemoto","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Iryo Sosei University, Iino, Chuo-dai, Iwaki 970-8551, Fukushima, Japan"},{"name":"Research Institute of Innovative Medicine, Tokiwa Foundation, Iwaki 971-8112, Fukushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Sawada","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Iryo Sosei University, Iino, Chuo-dai, Iwaki 970-8551, Fukushima, Japan"},{"name":"Research Institute of Innovative Medicine, Tokiwa Foundation, Iwaki 971-8112, Fukushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5564-1695","authenticated-orcid":false,"given":"Shigeaki","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Iryo Sosei University, Iino, Chuo-dai, Iwaki 970-8551, Fukushima, Japan"},{"name":"Research Institute of Innovative Medicine, Tokiwa Foundation, Iwaki 971-8112, Fukushima, Japan"},{"name":"School of Medicine, Fukushima Medical University, Fukushima 960-1295, Fukushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"106732","DOI":"10.1016\/j.jsbmb.2025.106732","article-title":"A comprehensive perspective on the role of vitamin D signaling in maintaining bone homeostasis: Lessons from animal models","volume":"250","author":"Rillaerts","year":"2025","journal-title":"J. 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