Thyroid diseases, as common disorders of the endocrine system, include autoimmune thyroid diseases (such as Hashimoto’s thyroiditis and Graves’ disease), thyroid dysfunction (hyperthyroidism, hypothyroidism), and thyroid cancers. Their pathogenesis involves the interaction of multiple factors, including genetics, environment, and immunity (1, 2). With the advancement of molecular medicine, the regulatory role of nutritional vitamins in the occurrence and progression of diseases has become a major research focus. In particular, the understanding of vitamin D’s functions has expanded beyond its traditional role as an essential micronutrient. It has now been confirmed to act in multiple capacities, such as a molecular cofactor, metabolic regulator, gene expression modulator, and epigenetic modifier. Through these diverse mechanisms, vitamin D helps coordinate the maintenance of cellular homeostasis and modulates key biochemical pathways involved in combating metabolic disorders, inflammatory responses, and immune regulation (3). Among the numerous vitamins, the research on vitamin D has attracted particular attention. It not only participates in calcium-phosphorus metabolism and bone health, but also plays important roles in immune regulation, cell proliferation, and differentiation. In recent years, the pathophysiological role of vitamin D in thyroid diseases has attracted widespread attention and the correlation between vitamin D deficiency and thyroid diseases is well established (4). Vitamin D not only participates in calcium-phosphorus metabolism and bone health but also plays important roles in immune regulation, cell proliferation, and differentiation. A large body of studies suggest that vitamin D may be involved in the development and progression of multiple thyroid diseases by inhibiting the proliferation and differentiation of thyroid cancer cells, modulating immune balance, suppressing autoantibody production, and affecting thyroid cell function (5–8). Additionally, epidemiological data indicate a higher prevalence of thyroid diseases in populations with vitamin D deficiency, though the exact mechanisms remain unclear (9). Furthermore, based on the concept of precision medicine, vitamin D has gradually evolved into an important tool in this field. It contributes to predicting, preventing, and delivering personalized treatments for chronic conditions such as cardiovascular diseases, diabetes, cancer, and neurodegenerative disorders. Among these advances, innovations in precision nutrition, including personalized vitamin D supplementation, have shown promise in improving treatment adherence and enhancing therapeutic outcomes (3). Therefore, this review aims to summarize the latest research progress on the association between vitamin D and thyroid diseases, explore the potential mechanisms of vitamin D deficiency in thyroid disorders, and integrate precision medicine technologies to provide a theoretical foundation for the clinical prevention and treatment of thyroid diseases.

The thyroid gland is a vital endocrine organ located in the neck, just below the thyroid cartilage. Shaped like a butterfly, it is responsible for the production and release of thyroid hormones, thyroxine (T4) and triiodothyronine (T3), which play key roles in regulating metabolism, growth, development, and other physiological function (10). Thyroid disorders refer to a group of diseases characterized by abnormal thyroid function or structural changes. In the past few years, the prevalence of thyroid diseases has gone up substantially, evolving into a crucial global health problem (1). Thyroid disorders are broadly classified into the following categories: hyperthyroidism, hypothyroidism, thyroid autoimmune disorders, thyroid nodules, and thyroid cancers (11). Among them, the incidence of thyroid autoimmune disorders (e.g., Hashimoto’s thyroiditis, Graves’ disease) and thyroid cancer is considerably higher among women than among men, which may be related to estrogen levels and X-chromosome immunity genes (12, 13). This sex-related disparity in the occurrence of thyroid diseases further highlights the imperative need to enhance early screening and develop personalized treatment approaches to reduce the overall disease burden.

Vitamin D is a multifunctional steroid hormone that is synthesized in the skin as a result of exposure to sunlight, and to a smaller degree, it can be obtained from the food we consume. In turn, skin and dietary vitamin D is converted to 25-hydroxyvitamin D [25(OH)D] or calcidiol by the liver enzymes 25-hydroxylase (CYP27A1 and CYP2R1). The inactive 25(OH)D is the primary circulating and storage form of vitamin D, which needs to be converted to the circulating biologically active compound 1,25-dihydroxyvitamin D (calcitriol) [1,25(OH)2D] by 1α-hydroxylase in the kidney to fulfill the physiological role of vitamin D (26, 27). Traditionally recognized for its crucial role in governing bone metabolism and maintaining calcium-phosphate balance, emerging proof indicates that vitamin D also exhibits extra-skeletal functions. These include modulating autoimmune disorders, cancer, metabolic syndrome, cardiovascular diseases, and diabetes (28, 29). Furthermore, 1, 25(OH)2D3 has been demonstrated to play significant roles in immune function across various cell types (e.g., lymphocytes, endothelial cells, osteoblasts, and keratinocytes), as well as in the control of cell growth and differentiation. Consequently, the pleiotropic functions of vitamin D include growth and bone calcification, immune system modulation, insulin secretion regulation, control of cellular proliferation, stimulation of cell differentiation, induction of apoptosis, safeguarding of calcium - phosphate stability, and regulation of muscular calcium transport (30, 31). For example, during the last few years, the relationship between vitamin D and thyroid diseases has received widespread attention, and several research findings have revealed that vitamin D inhibits the onset and development of thyroid cancer through multiple mechanisms: inhibiting tumor cell proliferation; triggering apoptosis; regulating cell cycle progression; inhibiting oncogenic signaling pathways (e.g., Wnt/β-catenin) (32). Furthermore, in the field of molecular genetics, studies have shown that the transcription factor VDR serves as the sole high-affinity target for 1,25(OH)₂D. This finding indicates that the functional characteristics of VDR are almost identical to those of vitamin D. Moreover, vitamin D has been proven to exert an impact on the epigenome by regulating transcription factor binding, histone modification, chromatin remodeling, and three-dimensional chromatin organization, thereby altering the chromatin accessibility and transcription of genes associated with immunity, inflammation, cell apoptosis, and metabolism (33). In addition, it can also bind the vitamin D receptor (VDR) to modulate the immune cells, inhibit Th1 and Th17 cell differentiation, and promote Th2 and Treg cell activity, thus reducing the thyroid autoimmune response as well as affecting thyroid function.

The influence of vitamin D on the development and progression of thyroid cancer is well documented. A clinical study involving 235 patients with papillary thyroid carcinoma (PTC) and 108 healthy controls demonstrated that, compared with the healthy control group, 166 out of the 235 thyroid carcinoma patients had significantly decreased serum levels of 25-hydroxyvitamin D (104). Furthermore, in another clinical study enrolling 548 patients with PTC, preoperative serum levels of 25-hydroxyvitamin D were also found to be significantly lower in patients with tumor diameter >1 cm and/or tumor metastasis (105). Correspondingly, a prospective cohort study revealed significantly lower serum levels of 25-hydroxyvitamin D in patients with PTC compared with healthy controls, based on a direct comparison of serum vitamin D concentrations between the two groups (106). In contrast, in a study involving 100 patients who underwent total thyroidectomy found that patients with vitamin D deficiency during the perioperative period were more likely to have thyroid malignancies in their postoperative histopathological evaluations (107). Moreover, numerous studies have also demonstrated low levels of serum 25(OH)D, as well as a reduction in its conversion to 1,25(OH)2D3 function, increase the risk of thyroid malignancy (108). However, the results across studies remain highly controversial. Some studies have reported no significant difference or no association in serum 25-hydroxyvitamin D levels when comparing experimental and control groups (108–111). But, these studies are not without limitations—for example, marked age disparities between the control and case groups, as well as an uneven distribution of disease subtypes—which may render their results susceptible to confounding bias. Thus, based on aforementioned research, vitamin D deficiency and decreased circulating osteotriol are associated with the development and progression of thyroid cancer (Table 1). Therefore, it appears reasonable to consider vitamin D supplementation as a cancer preventive strategy, both for reducing the risk of disease onset and as a secondary chemopreventive measure to inhibit disease progression (112). From the perspective of nutrigenomics, vitamin D acts as a key epigenetic regulator that mediates nutriment-gene interactions by modulating the epigenetic status of thyroid cancer-related genes, thereby achieving dynamic regulation of tumorigenesis and progression (113, 114). For instance, accumulating evidence indicate (115, 116) that DNA methylation represents a crucial epigenetic mechanism through which vitamin D modulates the expression of thyroid cancer-associated genes. Chronic vitamin D deficiency can upregulate the activity of DNA methyltransferases (DNMTs), thereby inducing hypermethylation in the promoter regions of VDR target genes (e.g., E-cadherin). This hypermethylation event suppresses gene transcription, ultimately leading to the undifferentiated state of tumor cells with potent oncogenic potential. Conversely, adequate vitamin D intake inhibits DNMTs activity, reduces the methylation levels of tumor suppressor genes, restores their transcriptional expression, and facilitates cellular differentiation. These findings highlight the critical role of early vitamin D intervention in the prevention of thyroid cancer. For example, according to a recent meta-analysis, it suggests that increasing serum 25(OH)D concentrations through supplementation may help reduce cancer-related mortality (117). Consistent with these findings, a zoological study (118) also demonstrated that vitamin D supplementation reduced tumor growth rate, diminished tumor size, and inhibited tumor progression. In this mouse model study, the animals were divided into two groups: one group received vitamin D supplementation, while the other did not. The results showed that tumor growth was significantly slower in the vitamin D-supplemented group compared with the control group. The underlying mechanism is thought to involve vitamin D supplementation regulating cellular signaling pathways, promoting apoptosis, and inhibiting angiogenesis—effects that restrict the blood supply to tumors, thereby suppressing cancer cell growth and gradually reducing tumor volume. However, the efficacy of vitamin D supplementation is contingent upon dosage and treatment timing. To translate these preclinical findings into cancer prevention and treatment strategies for humans, extensive further research and well-designed clinical trials are required to validate its potential and safety (119, 120). Therefore, when determining the optimal clinical dosage of vitamin D for the chemoprevention of thyroid cancer, it is imperative to incorporate nutrigenomics-based precision medicine approaches and tailor therapeutic regimens according to individual patient responses. Precision medicine aims to customize prevention and treatment strategies based on individual variability in genetics, environment, and lifestyle. Its integration with vitamin D nutritional interventions is reflected in etiology-specific interventions and biomarker-guided personalized therapies (121). However, extensive observational studies and controlled clinical trials are required to evaluate the optimal individualized anticancer efficacy of vitamin D analogs across distinct etiological mechanisms and specific biomarkers. A study focusing on vitamin D-mediated interventions for disease prevention and treatment under the framework of precision medicine emphasized the need for individualized therapeutic regimens tailored to the specific etiologies or pathophysiological pathways of different cancer types (119). For instance, in prostate cancer, vitamin D deficiency promotes β-catenin-mediated epithelial-mesenchymal transition (EMT), thereby enhancing tumor invasiveness. To target this specific pathogenic mechanism, high-dose vitamin D₃ (40,000 IU/day) can inhibit the Wnt/β-catenin pathway and reduce tumor invasiveness, but this therapeutic effect is only observed in patients with the wild-type VDR gene. In contrast, carriers of the VDR FokI polymorphism require combined treatment with CYP24A1 inhibitors to prevent the metabolic inactivation of vitamin D. This underscores the intervention logic of integrating etiological mechanisms with genotypic profiles (122, 123). Additionally, in colorectal cancer, targeting the etiology of inflammation-driven intestinal epithelial carcinogenesis, vitamin D supplementation exerts a risk-reduction effect in Asian populations by inhibiting the NF-κB pathway. Notably, this preventive effect is more pronounced in proximal colon cancer, where inflammation-driven characteristics are more prominent, than in distal colon cancer, which exemplifies the specificity of interventions based on both etiological mechanisms and lesion locations (119). However, whether these pathogenic mechanisms are also operative in thyroid cancer remains an open research question. Secondly, for biomarker-guided personalized dosing strategies, VDR expression levels and serum 25(OH)D serve as core predictive biomarkers for treatment efficacy in the field of cancer. For instance, in oral cancer patients with high VDR expression, calcitriol supplementation reduces the risk of tumor recurrence. In contrast, those with low VDR expression require combination with chemotherapy to enhance treatment efficacy (124). In colorectal cancer patients, higher 25(OH)D levels correlate with lower cancer incidence and mortality rates. Specifically, each 20 nmol/L increase in serum 25(OH)D is associated with a 12% reduction in colorectal disease-specific mortality and a 7% reduction in all-cause mortality (125). Therefore, accumulating evidence indicates that maintaining serum 25(OH)D levels within the range of 75–100 nmol/L maximizes the risk reduction for colorectal cancer (126). Based on this, a stepwise dosing regimen guided by baseline 25(OH)D levels has been clinically established: for patients with vitamin D deficiency (≤20 ng/mL), an initial dose of 50,000 IU/week is administered for 8 weeks, followed by a maintenance dose of 1,000–2,000 IU/day; for those with insufficiency (21–29 ng/mL), a daily dose of 1,000–2,000 IU is given directly; for those with sufficiency (≥30 ng/mL), routine supplementation is unnecessary. This strategy enables approximately 90% of patients to reach the target level (≥30 ng/mL) within 6 months, with an adverse reaction rate of less than 1%, fully demonstrating the clinical value of biomarker-guided precision dosing in improving efficacy and ensuring safety (119, 127).

In addition, vitamin D supplementation has been found to have a potential positive effect on thyroid function. Research in this area has been focused primarily in patients with autoimmune thyroid disease, with multiple clinical studies reporting low vitamin D levels in individuals affected by these disorders. These findings suggest a possible link between vitamin D insufficiency and thyroid autoimmunity (Table 2). Earlier studies have demonstrated a significantly higher incidence of AT (Autoimmune Thyroid disease) in patients with vitamin D deficiency, likely due to the association between reduced vitamin D levels and elevated thyroid-stimulating antibodies (TSAb), as well as goiter formation (128–132) (Table 2). Numerous researches have reported a significant inverse correlation between antithyroid peroxidase antibodies (TPOAb), antithyroglobulin antibodies (TgAb), and serum 25-hydroxyvitamin D (133) (Table 3) (134, 135). Notably, individuals with vitamin D deficiency exhibit a higher prevalence of positive TPOAb titers. Moreover, a study has found that after 12 months of vitamin D supplement, participants who received the supplement had significantly lower levels of TPOAb, TgAb, thyrotropin, thyroid hormone, and thyroglobulin in their serum (136), and a notable decrease in the dimensions of both thyroid lobes (137) (Table 4) (136, 138–140). Therefore, short-term high-dose oral vitamin D supplementation has been shown to reduce TPOAb and TgAb titers, suggesting its potential as a novel approach to improving thyroid function. However, there are currently no universal guidelines for vitamin D supplementation in patients with thyroid disorders. Moreover, significant variations exist in the dosage and treatment duration across different research cohorts, resulting in a lack of unified reference standards for clinical practice (141). For instance, study designs vary significantly in vitamin D dosage and intervention duration, impeding cross-study comparisons. Moreover, marked interindividual differences exist among participants of different ages and regional origins, contributing to the heterogeneity of experimental results (142). This heterogeneity is not only attributable to the diversity of study designs, but also linked to factors such as thyroid disease subtypes, comorbidities, and physical constitution, which significantly impairs the reliability of therapeutic evidence and its value for clinical translation. Furthermore, VDR expression in individuals is modulated by genetic and environmental factors. Thus, it is hypothesized that genetic variations in the VDR gene may lead to differential responses to vitamin D supplementation. A study investigating the effects of VDR gene polymorphisms indicated that the variant allele of VDR TaqI polymorphism and the FF genotype of VDR FokI polymorphism are associated with better responses to vitamin D supplementation, whereas the VDR BsmI and ApaI polymorphisms show no correlation with such responses (143). However, this study has certain limitations, mainly true genetic heterogeneity between different samples and incomplete data in genetic association research. Clinically, long-term excessive vitamin D supplementation may trigger a series of adverse reactions. Moreover, owing to metabolic disorders, patients with thyroid diseases are more susceptible to such toxicity, and excessive vitamin D intake elevates the risk of hypercalcemic toxicity. Therefore, the safety of vitamin D supplementation therapy deserves particular attention, and future researchers need to conduct large-sample, multicenter prospective cohort studies to define the safe dosage range of vitamin D supplementation for patients with different types of thyroid diseases.

VDRs are widely distributed in most human tissues and cells. Beyond its role in bone metabolism and calcium-phosphorus homeostasis, vitamin D plays a significant role in autoimmune diseases, cancer, and metabolic syndromes. In this review, we have explored the association between vitamin D and thyroid disorders, together with its underlying mechanisms of action. Additionally, we analyzed the possible protective effects of vitamin D supplementation on thyroid cancer and evaluated its impact on thyroid function. Based on the analysis of the aforementioned studies, vitamin D exerts a beneficial effect on thyroid cancer progression by directly inhibiting the proliferation, invasion, and metastasis of malignant thyroid cells through interactions involving VDR-mediated signaling pathways, genetic regulation, epigenetic modulation, and transcription factor regulation. Meanwhile, vitamin D can also modulate the immune system and suppress the immune response involved in thyroid autoimmune diseases, thus reducing the disease incidence and improving the function of the thyroid gland. Furthermore, vitamin D can indirectly inhibit the incidence of thyroid autoimmune diseases and thyroid cancer by regulating the homeostasis of intestinal flora through the thyroid-endocrine-intestinal axis. (Table 5) Consequently, vitamin D deficiency is increasingly recognized as a risk factor for a range of thyroid diseases, including autoimmune thyroid disorders and thyroid cancer.

The pleiotropic effects of vitamin D have been demonstrated in numerous studies, providing evidence of its protective role against thyroid carcinoma and the inhibitory effects of pharmacological 1,25(OH)₂D or its analogs on thyroid cancer cell proliferation. Meanwhile, nearly all studies investigating the impact of vitamin D supplementation on thyroid function have reported reduced levels of anti-thyroid antibodies following vitamin D supplementation. However, the limited number of published intervention studies in this field has resulted in ongoing controversy surrounding the preventive and therapeutic potential of vitamin D or its analogs in thyroid diseases. To substantiate this view, numerous large-scale multicenter studies are needed to evaluate the clinical impact of vitamin D supplementation on thyroid disease. Furthermore, this article also elaborates on interindividual differences in the personalized treatment of nutritional vitamin D and highlights strategies for translating precision medicine into clinical practice. However, the optimal dosage of vitamin D supplements remains to be determined, and further investigations via observational studies and long-term follow-up randomized controlled trials are required to fully validate its potential for precision therapy in thyroid diseases.