Vitamin D as a cellular endocrine system: Tissue-specific microcircuits, immune reprogramming, and metabolic resistance

Circulating 25-hydroxyvitamin D is the standard marker of vitamin D status, but tissue responses to vitamin D vary across organs, inflammatory states, and clinical settings. This review frames vitamin D biology as a cellular endocrine system in which substrate transport, local CYP27B1-mediated activation, CYP24A1-mediated inactivation, and VDR responsiveness form tissue-specific microcircuits. Evidence from barrier epithelia, immune cells, and brain-resident cells indicates that megalin/cubilin-dependent uptake, local enzyme balance, redox state, and downstream transcriptional competence can decouple serum 25-hydroxyvitamin D from intracellular vitamin D activity. We use metabolic vitamin D resistance to describe acquired low-responsiveness states driven by inflammation, aging, redox stress, or chronic disease. This framework clarifies biomarker interpretation and supports more context-aware approaches to supplementation, trial design, and tissue-targeted intervention.