Vitamin D–VDR Signaling Across Thyroid Disorders: A Systematic Review of Molecular Mechanisms, Autoimmunity, Genetic Susceptibility, Experimental Evidence and Therapeutic Translation

Vitamin D–Vitamin D receptor (VDR) signaling extends beyond calcium-phosphate homeostasis and regulates immune tolerance, inflammation, cellular differentiation, oxidative stress, and endocrine physiology. This systematic review evaluated the relationship between vitamin D–VDR signaling and thyroid disorders, including hypothyroidism, hyperthyroidism, Hashimoto’s thyroiditis, Graves’ disease, thyroid autoimmunity, genetic susceptibility, experimental mechanisms, and therapeutic implications. This study was conducted and reported in accordance with the PRISMA 2020 statement. PubMed/MEDLINE and Scopus were searched for studies published from January 2005 through June 2026, supplemented by backward and forward citation screening of relevant studies and reviews. Eligible evidence included human observational and interventional studies, genetic investigations, and relevant animal and in vitro studies addressing vitamin D status, vitamin D exposure or supplementation, VDR variation, vitamin D metabolism, or vitamin D–VDR mechanisms in relation to thyroid function, thyroid disease, thyroid autoantibodies, or related biological outcomes. A total of 13,623 records were identified, of which 11,730 unique records underwent title and abstract screening, 449 reports were assessed at the full-text stage, and 118 primary studies were included in the final synthesis. Because of substantial heterogeneity in populations, study designs, vitamin D exposures, outcomes, genetic backgrounds, and experimental models, findings were synthesized narratively rather than by quantitative meta-analysis. Lower circulating 25-hydroxyvitamin D [25(OH)D] concentrations were frequently associated with thyroid disease, particularly autoimmune phenotypes, and increased thyroid peroxidase and thyroglobulin antibodies in Hashimoto’s thyroiditis. Interventional evidence suggests that vitamin D supplementation may reduce thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) concentrations in some patients with autoimmune thyroid disease. However, these laboratory changes represent immunological surrogate outcomes and should not be interpreted as evidence of restored thyroid function, prevention of progression to overt hypothyroidism, reduced dependence on thyroid hormone replacement, or sustained clinical remission. Randomized evidence does not establish a general preventive effect of vitamin D supplementation on incident hypothyroidism. Associations between VDR polymorphisms, including FokI/rs2228570, rs1544410, rs731236, and rs7975232, and thyroid autoimmunity were inconsistent across populations. Experimental evidence implicates immune regulation, Th17/Treg balance, inflammatory signaling, vitamin D metabolism, and calcium-phosphate homeostasis. The evidence was limited by substantial clinical, methodological, and biological heterogeneity, frequent reliance on observational studies, population-specific genetic findings, and differences between experimental models and human thyroid physiology. Overall, vitamin D–VDR signaling represents a biologically plausible modifier of thyroid disease, but current evidence does not establish universal causality or therapeutic efficacy.