In our study, a significant linear association was observed between TB and SII, which showed a pronounced negative correlation. Even after controlling for relevant confounding variables, this negative correlation remained statistically significant. Further stratification of the samples based on factors such as gender, education, BMI, PA, smoking state, and diabetes, confirmed the persistence of this negative correlation across different strata. However, heterogeneity was observed among different age, race, hypertension, and drinking state groups, which necessitates further studies to elucidate the underlying mechanisms. In summary, the findings from this study provide additional evidence about the anti-inflammatory properties of bilirubin.

SII, a novel immune-inflammatory marker, quantifies the interaction between systemic inflammation and the human immune response. A past study demonstrated that SII exhibited better sensitivity, specificity, and predictive value for evaluating the severity of pancreatitis than the platelet lymphocyte ratio and neutrophil-to-lymphocyte ratio [7]. Apart from serving as a prognostic and predictive indicator for inflammatory diseases [8,9,10,11], SII can be used to assess the prognosis of certain cancers, such as colorectal [21], liver [7], cervical [22], biliary tract [23], and bladder cancer [24]. As SII encompasses lymphocyte, neutrophil, and platelet counts, it incorporates three indicators, thereby potentially offering a comprehensive assessment of the systemic immune-inflammatory status that considers a spectrum of immune and inflammatory activities.

Several studies have suggested that bilirubin possesses anti-inflammatory effects and can be used to treat inflammatory diseases. We found that bilirubin alleviated tissue damage under inflammatory stimuli by inhibiting the expression of inducible nitric oxide synthase and stimulating the production of local prostaglandin E2 [25]. Moreover, recent studies involving animal models of sepsis have shown that bilirubin inhibits the expression of proinflammatory cytokines and increases the levels of anti-inflammatory cytokines in the lungs, thereby alleviating tissue damage in sepsis [26]. In addition, bilirubin can downregulate the expression of adhesion molecules, inhibit inflammatory cell infiltration, reduce nitric oxide synthesis, and attenuate the production of various inflammatory factors. This anti-inflammatory activity has been demonstrated in animal models of endotoxemia, sepsis, and ischemia–reperfusion injury [27].

Evidence suggests that moderately elevated levels of bilirubin exert a protective effect against oxidative stress-related diseases [28]. Moreover, mild hyperbilirubinemia may induce beneficial adaptive responses, particularly during sepsis and other critical illnesses [29]. In our study, the total bilirubin levels were negatively linearly correlated with SII, indicating a potential anti-inflammatory role of bilirubin. However, high concentrations of bilirubin are harmful to the body and may cause neurotoxicity, myocardial damage, and organ injury such as to the liver and kidneys [14, 15, 30, 31]. Therefore, further elucidation is needed based on whether the anti-inflammatory effect of high-concentration bilirubin manifests as a linear correlation.

Currently, clinical studies have observed a negative correlation between bilirubin levels and the risk of certain diseases. Since 1994, Schwertner et al. and others have reported that low serum bilirubin levels are associated with an increased risk of coronary artery disease, peripheral arterial atherosclerotic disease, and coronary artery calcification [28, 32, 33]. In addition, bilirubin has been reported to play a protective role in various diseases such as metabolic syndrome [34], diabetes and its complications [35, 36], and obesity [37]. The findings from these studies collectively suggest the potential therapeutic value of bilirubin under several clinical conditions. The present study revealed a negative correlation between TB and SII, providing further evidence for the anti-inflammatory effect of bilirubin and suggesting its potential protective role in inflammation-related diseases.

The concentration of bilirubin is associated with various factors, including age, sex, race, obesity, and smoking [38]. To minimize the potential impact of these factors on the results of our study, several potential confounding variables were adjusted, which included age, sex, race, education level, BMI, PA, smoking status, drinking status, diabetes, and hypertension. Additionally, the association between TB and SII was stratified based on the abovementioned confounding variables. The significant negative correlations between TB and SII were evident in most subgroups. Our results allude that the association between TB and SII is not significant in participants aged ≥ 65 years. Previous studies have observed that bilirubin levels increase with age [39] and that higher serum bilirubin levels are associated with a lower likelihood of functional dependence in older adults [40], implying the potential protective effect of bilirubin in the elderly. Nevertheless, with advancing age, most individuals tend to develop a chronic low-grade proinflammatory state, and the elderly often exhibit mild proinflammatory features [41]. Therefore, the heterogeneity within the elderly population may lead to a lack of significant correlation between bilirubin levels and SII, and the specific mechanisms need to be further clarified.