{"doi":"10.3389/fimmu.2026.1770141","title":"Vitamin D3 as an immunomodulatory agent: molecular mechanisms, clinical translation, and precision therapeutic strategies","abstract":"<jats:p>\n                    Vitamin D\n                    <jats:sub>3</jats:sub>\n                    (VitD\n                    <jats:sub>3</jats:sub>\n                    ) 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 D\n                    <jats:sub>3</jats:sub>\n                    orchestrates immune homeostasis through vitamin D receptor (VDR) signaling, exerting profound regulatory effects on both innate and adaptive immunity. Mechanistically, Vitamin D\n                    <jats:sub>3</jats:sub>\n                    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 D\n                    <jats:sub>3</jats:sub>\n                    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\n                    <jats:italic>VDR</jats:italic>\n                    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 D\n                    <jats:sub>3</jats:sub>\n                    , 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.\n                  </jats:p>","journal":"Frontiers in Immunology","year":2026,"id":619442,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1598531,"name":"Zhenzi Li","orcid":null,"position":1,"is_corresponding":false},{"id":1032013,"name":"Shaojie Li","orcid":"0000-0001-6791-3216","position":2,"is_corresponding":false},{"id":544134,"name":"Yue Li","orcid":"0000-0003-2991-970X","position":3,"is_corresponding":false},{"id":851709,"name":"Haifeng Pan","orcid":"0000-0002-6950-3867","position":4,"is_corresponding":false},{"id":1053720,"name":"Ye Tao","orcid":"0000-0003-1043-6687","position":5,"is_corresponding":false},{"id":1267789,"name":"Qing Liu","orcid":"0000-0002-7046-0307","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Vitamin D3 as an immunomodulatory agent: molecular mechanisms, clinical translation, and precision therapeutic strategies","abstract":"<jats:p>\n                    Vitamin D\n                    <jats:sub>3</jats:sub>\n                    (VitD\n                    <jats:sub>3</jats:sub>\n                    ) 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 D\n                    <jats:sub>3</jats:sub>\n                    orchestrates immune homeostasis through vitamin D receptor (VDR) signaling, exerting profound regulatory effects on both innate and adaptive immunity. Mechanistically, Vitamin D\n                    <jats:sub>3</jats:sub>\n                    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 D\n                    <jats:sub>3</jats:sub>\n                    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\n                    <jats:italic>VDR</jats:italic>\n                    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 D\n                    <jats:sub>3</jats:sub>\n                    , 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.\n                  </jats:p>","is_dataset_classified":null,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41846928","pmcid":"PMC12989342","openalex_id":"https://openalex.org/W7133234124","authors":[],"funders":[],"total_grants":0,"fwci":45.9465,"citation_percentile":0.99908341,"influential_citations":0,"citation_trend":[{"year":2026,"count":6}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://public-pages-files-2025.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1770141/pdf","host_type":"journal"},{"url":"https://public-pages-files-2025.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1770141/pdf","host_type":"publisher"},{"url":"https://www.frontiersin.org/articles/10.3389/fimmu.2026.1770141/full","host_type":"publisher"},{"url":"https://doi.org/10.3389/fimmu.2026.1770141","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41846928","host_type":"repository"},{"url":"https://doaj.org/article/12a7727b0f514945a5c5e0dab061a96f","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12989342/","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12989342","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12989342?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Vitamin D Research Studies","Psoriasis: Treatment and Pathogenesis","Vitamin C and Antioxidants Research","Humans","Cholecalciferol","Animals","Precision Medicine","Immunomodulating Agents","Receptors, Calcitriol","Immunologic Factors","Immunomodulation","Signal Transduction","Translational Research, Biomedical","Immunity, Innate"],"mesh_terms":["Immunomodulating Agents","Animals","Cholecalciferol","Humans","Immunity, Innate","Immunologic Factors","Signal Transduction","Receptors, Calcitriol","Immunomodulation","Translational Research, Biomedical","Precision Medicine"],"keywords":["Vitamin D and neurology","Cathelicidin","Immune system","Calcitriol receptor","Rheumatoid arthritis","vitamin D deficiency","Vitamin","Inflammation","Disease","Immunomodulation","Autoimmune diseases","Vitamin D3","drug delivery systems","Precision Medicine","Inflammation Regulation","Vdr Signaling"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"refsnp"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T07:11:33.429864Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}