Vitamin D3 as an immunomodulatory agent: molecular mechanisms, clinical translation, and precision therapeutic strategies

Vitamin D₃ (VitD₃) deficiency affects over one billion individuals globally, representing a critical modifiable risk factor for immune-mediated diseases. Beyond its classical role in calcium metabolism, Vitamin D₃ orchestrates immune homeostasis through vitamin D receptor (VDR) signaling, exerting profound regulatory effects on both innate and adaptive immunity. Mechanistically, Vitamin D₃ maintains the balance between antimicrobial defense and inflammatory suppression by inhibiting key pro-inflammatory pathways including nuclear factor κB (NF-κB) and the NOD-like receptor protein 3 (NLRP3) inflammasome, while activating the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)-mediated antioxidant defense system. However, the immunomodulatory effects of Vitamin D₃ exhibit significant inter-individual variability, with clinical efficacy highly dependent on patient-specific factors including serum 25-hydroxyvitamin D [25(OH)D, calcifediol] levels and <i>VDR</i> gene polymorphisms, driving a paradigm shift from empirical supplementation toward biomarker-guided precision medicine. Novel delivery systems-nanoemulsions, twin-screw extrusion technology, and liposomes-effectively overcome bioavailability and stability limitations of traditional preparations. This review systematically examines the immunomodulatory mechanisms of Vitamin D₃, evaluates clinical translation evidence in psoriasis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes mellitus (T1DM), inflammatory bowel disease (IBD), and discusses precision medicine strategies and therapeutic potential.