Prostate cancer (PCa) ranks as the fifth highest number of cancer-related fatalities among men worldwide, with an estimated annual occurrence of around 1.3 million cases (1, 2). Despite advancements in early screening, regions such as Asia and South America continue to grapple with elevated PCa mortality rates (2). The progression of PCa is a highly intricate process, often spanning decades from the initiation of pathological changes to the manifestation of clinical symptoms (3). Several studies have identified associations between PCa development and factors such as age, race, metabolic syndrome, diabetes, and obesity (3–6). However, the latest study from the European Association of Urology on dietary factors found no conclusive evidence supporting an association between specific dietary factors and PCa development (7).

Vitamins are small-molecule organic compounds that complement the three macronutrients: carbohydrates, proteins, and lipids (8). Although vital for maintaining physiological homeostasis, many vitamins cannot be synthesized by the human body and must be obtained through diet or supplementation. However, evidence regarding the relationship between various vitamin intake and PCa risk remains insufficient, particularly for families such as the B vitamins (7, 9). For instance, the association between vitamins B9 and B12 and PCa remains controversial across different studies (10–13). Existing research on the relationship between vitamin A intake and PCa risk is scarce and has produced conflicting findings (14, 15). The effects of other vitamins are also inconclusive. Vitamin C, widely recognized for its antioxidant properties, may offer anticancer benefits, yet excessive intake may paradoxically promote oxidative stress (9). A dose–response meta-analysis by Gao et al. suggested an association between elevated circulating concentrations of 25-hydroxyvitamin D and increased PCa risk (16). Conversely, Pernar et al. (17) proposed that vitamin D may reduce PCa risk based on existing evidence. Similar controversies surround the effect of vitamin E and others on PCa risk (18–20). Although some in vitro and in vivo studies have demonstrated the antitumor activity of vitamin K, certain clinical and basic studies have also reported antitumor properties of vitamin K antagonists (21, 22).

The National Health and Nutrition Examination Survey (NHANES) provides data that accurately reflects the health and nutrition status across the nation, employing a multistage, stratified, randomized sampling approach. Hence, we undertake observational studies utilizing NHANES data to assess the association between vitamin intake and PCa risk, providing valuable recommendations for vitamin intake and PCa prevention.

This study is the first comprehensive investigation of the association between different types of vitamin intake and PCa risk based on large-scale observational study data. Specifically, we analyzed the association between the intake of 10 vitamins and PCa using NHANES data. The findings suggested that dietary retinol intake was positively associated with an increased risk of PCa. Additionally, there were inverse associations observed between supplemental vitamin B9 intake, supplemental vitamin B12 intake, and overall vitamin B12 intake with the risk of PCa.

Our cross-sectional study revealed an association between high dietary retinol intake and elevated PCa risk. Previous studies investigating the effect of retinol intake on PCa risk are limited and yield inconsistent results (14, 15). A case–control study conducted in Italy found no significant association between retinol and the risk of PCa (33). A study in southwestern Finland among adult male smokers found that higher serum retinol levels were associated with an increased risk of PCa (34). Our findings are also supported by a large prospective cohort study conducted in the United States involving more than 20,000 participants (35). Additionally, a case–control study in Europe reported a significant positive association between dietary retinol intake and an increased risk of PCa (36). Some studies on circulating retinol levels suggest that high concentrations of retinol may be beneficial in reducing PCa risk (37, 38). For instance, a large prospective study involving 30,000 men by Hada et al. (37) demonstrated higher levels of retinol were associated with an increased risk of PCa. Similarly, a recent case–control study in Singapore by Loh et al. (39) showed that increased retinol concentrations were positively associated with the overall risk of PCa. The potential mechanisms underlying the effect of retinol on PCa risk may include its contribution to tumorigenesis by promoting cell proliferation and dedifferentiation, thereby facilitating tumorigenesis (40). Given the potential regional differences, large-scale, multi-cohort studies are needed to further investigate these associations.

Our study found that supplemental intake of vitamins B1 and B2 was associated with a reduced risk of PCa. However, current epidemiological evidence regarding the relationship between these two vitamins and PCa is limited. Some studies have reported an inverse association between vitamin B1 intake and the risk of colorectal and esophageal cancers (41, 42). Additionally, a previous NHANES-based study identified a significant inverse correlation between vitamin B2 intake and prostate-specific antigen levels (43). Vitamin B1 may help maintain cellular homeostasis and reduce oxidative stress, while its deficiency could lead to DNA damage and impaired DNA repair capacity (44). Vitamin B2 may exert anti-PCa effects through its active form, flavin mononucleotide, which has been shown to compete with dihydrotestosterone for binding to the androgen receptor, thereby interfering with androgen signaling and exerting antitumor effects (45). Notably, the weak trends observed in our study suggest that the dose–response relationship may be non-linear or influenced by other factors. Therefore, we recommend future prospective cohort studies to improve the accuracy of exposure assessment, along with mechanistic studies to clarify the biological pathways involved. Additionally, future research should explore the effects of supplement form, dosage, and duration on PCa risk to provide more robust scientific evidence for nutritional strategies in PCa prevention. In the vitamin B family, our study revealed that vitamin B9 and B12 intake were negatively associated with PCa risk. Several studies have suggested that folic acid, a component of vitamin B9, may protect effects against PCa through mechanisms such as cytosine-phosphate islands, DNA uracil misincorporation, and methylation (46). Similarly, a case–control study by Shannon et al. (11) discovered a negative association between dietary folate intake and PCa risk, and other studies have suggest that higher folate levels may protect against elevated prostate-specific antigen levels (47). However, our study only showed a significant protective effect of vitamin B9 supplementation in PCa risk. The differences in bioavailability between supplemental and dietary vitamin B9 may help explain their varying associations with PCa risk. A randomized controlled trial (RCT) in lactating women found that 96% of those taking 400 μg/day of synthetic folic acid had detectable levels of unmetabolized folic acid (UMFA) in their breast milk, accounting for approximately 8% of the total milk folate concentration (48). In contrast, this phenomenon was not observed in women supplemented with the natural form, [6S]-5-methyltetrahydrofolate (5-methylTHF) (48). These findings suggest that the metabolic capacity for synthetic folic acid in the intestine and liver can be saturated, potentially leading to UMFA accumulation. Such accumulation may disrupt the body’s folate regulation mechanisms and downstream functions, such as folate-binding protein expression, ultimately affecting folate bioavailability in specific tissues. Additionally, dietary intake was self-reported by participants, which may introduce recall bias. Tio et al. (12) conducted a meta-analysis of 11 studies with 146,782 participants and found no association between dietary vitamin B9 and PCa risk. Similar findings were reported in a meta-analysis by Wang et al. (49), which aligns with our study results. Furthermore, our cross-sectional investigation revealed a negative correlation between supplemental vitamin B12 consumption and PCa risk. However, there is a lack of studies on the association between vitamin B12 intake and PCa risk. Although several studies have examined the link between circulating levels of vitamin B12 and the risk of PCa, their findings have been inconsistent (10, 13). It is hypothesized that vitamin B may influence cancer risk through its effects on DNA replication, methylation, and cellular damage repair (50). The intake of other B vitamins is not associated with PCa risk observed in population-based studies. Considering that cross-sectional studies are limited in their ability to establish causality, further large prospective population-based trials or RCTs are warranted to address the existing gap in this area.

Our study found no association between the intake of vitamin C or vitamin D and the risk of PCa. Vitamin C, known for its role as a reducing agent and scavenger of free radicals, has been suggested to have potential implications in anticancer treatment. However, two randomized trials found no link between vitamin C dietary intake or supplementation and PCa risk (51, 52). Similarly, a case–control study in Canada involving approximately 4,000 participants found no association between dietary intake or supplementation of vitamin C and the incidence of PCa (53). Vitamin D, which primarily regulates calcium and phosphorus metabolism, has been suggested to influence tumor development by regulating cell differentiation and apoptosis (54). Nevertheless, no association between vitamin D intake and PCa risk was found in this study. This aligns with recent systematic reviews and a large RCT (7, 55). It is important to note that dietary intake alone is not the only factor influencing vitamin D levels in the blood, and thus, the relationship between vitamin D intake and PCa risk warrants further exploration.

Vitamin E has shown antitumor activity in some preclinical studies due to its pro-apoptotic properties, but this has not been consistently observed in population studies (19, 51, 56). Similarly, our observational study found no association between vitamin E and PCa risk. Vitamin K is available in two natural forms, phylloquinone (vitamin K-1) and menaquinones (vitamin K-2), with the former serving as the primary dietary form derived from vegetable oils and vegetables (57). Preclinical evidence suggests that vitamin K may exert antitumor activity, as demonstrated in several in vitro and in vivo studies. For example, a prospective cohort study by Nimptsch et al. (58) discovered that menaquinones intake showed an inverse association with the risk of PCa (21). However, some studies have proposed that vitamin K antagonists may have antitumor properties, though these findings were not confirmed in a subsequent nested case–control study using the Danish Demographic and Health Data Register (22, 59, 60). In our study, no association between vitamin K intake and PCa risk was observed. The outcomes of a large cancer screening trial in the United States population conducted by Hoyt et al. indicated that intake of vitamin K did not affect the overall and advanced PCa risk in the US population (61). Mechanistically, vitamin K exerts its antitumor effects by enhancing oxidative stress and causing cell cycle arrest, while vitamin K antagonists inhibit peroxisome proliferator-activated receptor γ signaling, subsequently inhibiting AR signaling to suppress PCa (21, 62). Thus, the relationship between vitamin K and PCa remains elusive.

Our study exhibits several strengths that contribute to its reliability. Firstly, we employed a comprehensive set of factors as covariates in our observational study to minimize confounding effects, which strengthens the robustness of our results. Secondly, we utilized a nationally representative NHANES population, thereby ensuring the generalizability and statistical power of our analyses. However, our study also has limitations. Firstly, the methodological approaches correspond to populations from a multiracial US population, potentially limiting the generalizability of our findings. Secondly, certain vitamin species were excluded from the analysis due to data limitations. Furthermore, the design of this study limits our ability to infer the direction of causality between vitamin intake and PCa risk, raising the possibility of reverse causation. For instance, individuals may change their vitamin intake after being diagnosed with PCa or due to the presence of other health conditions. The inconsistency of results across models adjusted for different sets of covariates suggests that the findings should be interpreted with caution. Although the 24-h dietary recall is widely used in nutritional epidemiology, its reliance on self-reported data may introduce recall bias, potentially attenuating true associations. Confounding by indication may be present among supplement users, as individuals who choose to take supplements may differ systematically in health status or behavior compared to non-users. The absence of a clearly defined strategy for multiple comparisons increases the risk of type I error, which may lead to spurious associations. The sample size of PCa patients in this study is relatively small, which may affect statistical power and lead to result instability and potential bias. Although we have adjusted for several covariates, there may still be residual confounding factors that could impact the results. We observed that in the quartile-based analysis, the associations between certain vitamin intakes and the risk of PCa were not entirely consistent with the corresponding trend tests. In addition to factors such as sample size and potential confounding, this discrepancy may be attributed to limitations inherent in the statistical methods as well as the complex underlying biological mechanisms of vitamin metabolism. Since the data were log-transformed, the clinical interpretation of the results should be understood on the logarithmic scale. We recommend that future studies further consider standardizing measurement units during data processing to enhance interpretability and consistency of the findings. Considering that the dose–response relationship may exhibit more complex non-linear patterns, future studies should employ more sophisticated analytical methods, such as polynomial regression or piecewise regression, to more comprehensively elucidate deeper non-linear effects. Third, PCa status in our study was based on self-reported data, which is subject to potential recall bias and outcome misclassification. Participants may inaccurately recall or report their cancer diagnosis, particularly for diseases with long latency such as PCa. Misclassification of disease status could lead to underestimation or overestimation of true associations. Over-reporting among health-conscious individuals with higher supplement use might lead to an underestimation of the protective effect of vitamin B12, while under-reporting in individuals with high dietary retinol intake could exaggerate its apparent risk association. Due to methodological constraints, we did not evaluate the potential correlations among the intake of multiple vitamins. Future research should establish standardized metrics for vitamin intake and utilize prospective cohort studies and RCTs to comprehensively assess the combined effects of multiple vitamins.

In conclusion, our observational study suggests that dietary intake of retinol may increase the PCa risk, while supplemental intake of vitamin B9, vitamin B12, and total vitamin B12 intake are inversely associated with PCa risk. However, no significant associations were found between the intake of other vitamins and PCa risk. Due to the study design, we cannot establish definitive causality between vitamin intake and PCa risk. Future research should focus on high-quality, large-scale RCTs to strengthen the evidence for vitamin intake as a preventive measure for PCa.