Prostate cancer is the most common cancer in American men and the second leading cause of cancer-related deaths [16]. Therefore, early screening for PCa can help in early detection and early treatment to reduce mortality. Current screening of the PCa population is mainly based on PSA [17], and clarifying the factors affecting PSA is beneficial to improve the quality of screening. We used a nationally representative sample of US adult men to define the relationship between serum urea nitrogen and PSA. In addition, serum urea nitrogen has been reported in the literature to be associated with prostate cancer [10]. We hypothesized that serum urea nitrogen would also affect PSA levels. To test our hypothesis, the NHANES database was used to explore the relationship between serum urea nitrogen and PSA in US adults without a history of prostate tumors. By analyzing 5256 NHANES participants, we found that each 1ng/ml increase in serum urea nitrogen was associated with a 0.0325ng/ mL (log2 transformed) increase in PSA concentration (95% CI: 0.0064, 0.0586) with a P trend of less than 0.05. This result was confirmed by sensitivity analysis and is plausible.

Currently, an association between serum urea nitrogen and PCa has been documented. In the study of Tsutomu Nishiyama et al. on the effect of androgen deprivation therapy (ADT) on the metabolism of prostate cancer patients, it was found that serum urea nitrogen was measured before and 6 months after ADT treatment, and a significant increase in serum urea nitrogen (P = 0.03) was found, so it can be concluded that there is an essential association and role in androgen deprivation for prostate cancer [18]. In addition to this, in the results of Ugur Uyeturk et al. who studied serum reticulin levels in prostate cancer patients, it was found that there was a significant difference in serum blood urea nitrogen in the prostate cancer group and benign prostatic hyperplasia, and the results showed that blood urea nitrogen (p < 0.001) levels were significantly higher in the prostate cancer group than in the prostatic hyperplasia group, and from the results of this article, it can be speculated whether blood urea nitrogen plays a role in the development of prostate cancer plays an important role [19]. Some articles have reported that serum urea nitrogen (BUN) can be used as a prognostic indicator for cardiopulmonary vascular diseases, such as Jihong Fang et al. who found that the ratio of urea nitrogen to serum albumin may be a simple and useful prognostic tool for predicting mortality in critically ill patients with acute pulmonary embolism [11, 20], and BUN levels have been reported to be positively associated with the risk of type 2 diabetes mellitus in Chinese adults [21]. event risk in Chinese adults has been reported to be positively correlated [21]. Some scholars have even found that blood urea nitrogen can be used as a prognostic indicator for tumors, such as Kaiming Zhang and others who found that blood urea nitrogen as a biomarker in systemic oxidative stress can independently predict the prognosis of patients with surgical breast cancer in a prognostic study of breast cancer patients [22]. As for prostate cancer, it is worthwhile to further investigate and explore whether blood urea nitrogen can be used as its biomarker to provide new therapeutic tools for the treatment of prostate cancer.

There are regional differences in the incidence of prostate cancer, which may be due to differences in dietary habits. Nutrients, including fat, protein, carbohydrates, vitamins (vitamins A, D and E) and polyphenols, may influence the pathogenesis and progression of PCa by mechanisms including: inflammation, antioxidant effects and the action of sex hormones. Urea nitrogen is the main end product of protein metabolism in the body. Excessive protein catabolism or intake can lead to an increase in blood urea nitrogen in the body, and cancer is a wasting disease that increases protein consumption in the body, which increases blood urea nitrogen levels [ [23]. An animal study using a mouse model of PCa reported that high milk consumption showed a slight protective effect against PCa progression by decreasing the expression of Ki-67 and G protein-coupled receptor family C group 6 member A [24]. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are not only by-products of normal cellular metabolism but also play an important role in cellular signaling. However, when ROS and RNS levels are elevated, cells are exposed to oxidative stress, which activates various mechanisms that allow them to cope with these changes. Studies have shown that oxidative stress conditions play an important role in the development and progression of prostate cancer by regulating molecules such as DNA, enhancers, transcription factors and cell cycle regulators, and one study reported that total bilirubin (TBIL), lactate dehydrogenase (LDH), creatinine (CRE) and blood urea nitrogen (BUN) were significantly elevated in a mouse model of systemic oxidative stress [25]. After analysis, blood urea nitrogen is used as a systemic oxidative stress biomarker to assess the development and prognosis of prostate cancer.

The present study demonstrates several advantages. First, the highlight of this study is the large sample size. The study included a large number of 5256 participants, which provides a high statistical power to quantitatively assess the association between serum urea nitrogen and PSA levels. Secondly, we not only had to deal with different types of missing data, but also to consider the impact of missing data on the results, and finally, sensitivity analyses were performed on the missing data and the effect sizes were evaluated, and a generalized additive model (GAM) was used to verify that the linear relationship was accurate.

The current research work presents several limitations that must be considered when it comes to the results. First, the design of our study is cross-sectional in nature. Due to its inherent limitations, we were unable to derive a causal relationship between serum urea nitrogen and PSA, and it was difficult to distinguish between them causally. Second, the study population was limited to U.S. adults only, and thus the generalizability was geographically limited. Third, this study was based on a secondary analysis of published data and therefore could not adjust for variables not included in the dataset, such as dihydrotestosterone concentration. Fourth, we excluded users with male prostatitis, or recent prostate manipulation (i.e., rectal examination within 1 week, prostate biopsy, surgery, or cystoscopy within 1 month) and participants with malignancy because these special populations have a significant effect on PSA concentrations. Therefore, the results included in this study are not applicable to the aforementioned populations.