Vitamin D-Related Signaling and Epigenetic Regulation: Evidence from Experimental, Observational, and Interventional...

The active vitamin D metabolite, 1,25-dihydroxycholecalciferol [1,25(OH)₂D], exerts its biological effects through binding to the vitamin D receptor (VDR), a ligand-activated transcription factor regulating the expression of genes involved in calcium and phosphate homeostasis, immune modulation, and cell proliferation and differentiation. In addition to direct transcriptional regulation, 1,25(OH)₂D signaling also involves epigenetic mechanisms. A total of 90 studies were included in this narrative review, comprising experimental studies (n = 45), observational studies (n = 17), population-based studies (n = 8), interventional studies (n = 15), and mixed-design studies (n = 5). Experimental studies in cell cultures and animal models demonstrate that 1,25(OH)₂D may affect several major epigenetic regulatory pathways, including chromatin remodeling, DNA methylation, histone modifications, and the expression of non-coding RNAs, particularly microRNAs. Preclinical evidence suggests that the epigenetic actions of 1,25(OH)₂D are involved in metabolic regulation, immune responses, bone development, fibrotic processes, carcinogenesis, ageing, and fetal programming. However, evidence from observational studies and randomized controlled trials remains limited and inconclusive. Some studies have reported alterations in miRNA expression, methylation of selected loci, and epigenetic age markers. The clinical relevance of 1,25(OH)₂D-mediated epigenetic regulation has not yet been fully established. The interpretation of available findings is limited by substantial heterogeneity in study populations, exposure and intervention protocols, environmental factors, interindividual variability in response to vitamin D supplementation associated with genetic polymorphisms and methylation status, and the restricted range of analyzed cell types. This subject requires randomized controlled trials integrating molecular endpoints with clinically relevant outcomes.