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 VDR 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.