In this study, we conducted a two-sample MR analysis to explore the causal relationship between OSIBs and lung cancer risk. Our findings suggest that certain OSIBs, such as Albumin, MUFA, and Lactate, are significantly associated with lung cancer risk. Higher genetically predicted Albumin levels were associated with a reduced risk of adenocarcinoma, while elevated MUFA levels were linked to an increased risk of squamous cell carcinoma. Additionally, higher Lactate levels were positively correlated with small cell lung cancer risk. These results highlight the distinct roles of OSIBs in the development of different lung cancer subtypes.

It is worth noting, however, that none of these associations remained statistically significant after FDR correction. Nonetheless, this does not necessarily negate their potential biological relevance. In exploratory MR studies, FDR correction is typically used as a supplementary approach to support the robustness of the findings, rather than as a definitive filter—especially when exposures are correlated and the primary aim is to generate hypotheses for further validation.

These findings are consistent with existing literature on the role of OS in cancer development. OS, caused by the accumulation of ROS, is a well-established factor in the initiation and progression of various cancers, including lung cancer [13]. ROS induce DNA mutations, protein misfolding, and lipid peroxidation, which can all contribute to carcinogenesis [27]. Albumin, a major plasma protein with antioxidant properties, is believed to mitigate oxidative damage [28]. The protective effect of Albumin against adenocarcinoma risk observed in our study may be due to its role in buffering OS and maintaining cellular homeostasis. Lower levels of albumin in cancer patients have been linked to poorer prognosis, possibly because reduced antioxidant capacity allows for increased oxidative damage and tumor progression [29]. Adenocarcinoma, which is often associated with environmental and genetic factors such as smoking and mutations in EGFR and ALK genes, may be more susceptible to the protective effects of Albumin, which helps maintain cellular integrity in the presence of OS [30]. Our findings suggest that albumin may reduce adenocarcinoma risk by preventing DNA damage and inflammatory responses that are critical for tumor initiation and metastasis.

MUFAs, although often considered beneficial for cardiovascular health [31], can contribute to cancer development under certain conditions, particularly in lung cancer. MUFAs influence OS, inflammation, and lipid metabolism—factors central to cancer pathogenesis [32, 33]. High MUFA intake has been associated with increased lipid peroxidation, which leads to the production of reactive aldehydes and other toxic compounds that promote cancer cell proliferation and metastasis [34]. Additionally, MUFAs have been shown to alter tumor microenvironmental factors, such as inflammation and immune cell activation, that favor tumor progression. The increased risk of squamous cell carcinoma associated with higher genetically predicted MUFA levels in our study is consistent with these mechanisms. Squamous cell carcinoma often linked to smoking and environmental exposures, may be particularly responsive to altered lipid metabolism, making it more sensitive to the pro-inflammatory and oxidative effects of MUFAs [35, 36]. Our findings suggest that MUFAs could exacerbate squamous cell carcinoma development by enhancing oxidative damage and inflammatory pathways that promote tumorigenesis in this specific subtype.

The positive association between Lactate and small cell lung cancer risk is particularly noteworthy. Lactate, a byproduct of anaerobic metabolism in tumors, plays a crucial role in the Warburg effect, a hallmark of cancer metabolism [37]. In small cell lung cancer, which is characterized by its rapid growth and aggressive behavior, cells primarily rely on glycolysis even in the presence of oxygen, producing large amounts of Lactate [37, 38] Lactate not only serves as an energy substrate for proliferating cancer cells but also promotes tumor progression through several mechanisms [39]. It can stimulate angiogenesis, immune suppression, and metastasis—all of which are vital processes for aggressive cancer phenotypes like small cell lung cancer [37, 40]. Our study identified a genetically predicted positive association between lactate levels and small cell lung cancer risk. However, this result should be interpreted with caution, as the odds ratio was relatively high (OR = 4.565) and the confidence interval was wide (95% CI: 1.009–20.657), indicating substantial uncertainty and potential statistical instability. The wide confidence interval may reflect limited power or variability in the instrumental variables for lactate. Therefore, while this association is biologically plausible and aligns with existing knowledge of tumor metabolism, it requires validation in future independent studies with greater statistical power.Taken together, our findings suggest that lactate may contribute to the pathogenesis of small cell lung cancer through its metabolic functions. Nonetheless, these results are exploratory in nature and should not be overinterpreted. Further mechanistic and epidemiological studies are needed to confirm these observations and clarify the role of lactate in small cell lung cancer.

Conversely, other OSIBs, such as Hxa and Toc, did not show significant associations with lung cancer risk in our study. This could be explained by their differing roles in OS and metabolism across cancer subtypes. For example, Hxa, a purine metabolite, may not be directly involved in the OS pathways that drive lung cancer development, or its effects could be overshadowed by other more prominent biomarkers. Similarly, Toc, a form of vitamin E, acts as an antioxidant but may not have a strong impact on the pathophysiology of lung cancer compared to other biomarkers like albumin, MUFAs, or lactate. The lack of significant association between these OSIBs and lung cancer could reflect the complex nature of cancer metabolism, where a variety of factors interact to influence disease progression. Additionally, genetic variability in OS regulation may lead to differential associations across cancer subtypes, indicating the need for further research to explore how these biomarkers interact with genetic and environmental factors that influence lung cancer risk.

This study has several strengths, including the use of Mendelian randomization, which reduces biases typically found in observational studies, such as confounding and reverse causality. The bidirectional design of our MR analysis also allows us to assess potential reverse causation, an important consideration in complex diseases like cancer. The use of large-scale summary genetic data increases the statistical power and generalizability of our findings. However, there are several limitations. While MR is a powerful tool for causal inference, it assumes that genetic variants are not associated with confounders other than the exposure of interest. Despite rigorous quality control, horizontal pleiotropy—where genetic variants influence the outcome via alternative pathways—remains a potential concern. In addition, the genetic variants used were mainly derived from European populations, which may limit the generalizability of our findings to other ethnic groups. Future studies in more diverse populations are warranted. Our analysis was also restricted to the availability and scope of existing GWAS summary data, which limits the completeness of information on clinical characteristics, such as cancer staging, treatment strategies, and survival outcomes. Consequently, stratified or subgroup analyses could not be performed. Moreover, because the exposure and outcome data were obtained from different sources and potentially collected during different time periods, temporal alignment could not be fully ensured, which may affect the interpretation of causal estimates. Furthermore, although a range of associations were explored, none remained statistically significant after correction for multiple testing. While this raises concerns about potential false positives, it also highlights the conservative nature of such corrections, particularly in the context of correlated exposures. Lastly, the use of summary-level data precluded any investigation of interactions, mediation effects, or the role of time-varying exposures, which are important in clinical and epidemiological contexts.

In conclusion, our study provides evidence for a causal relationship between OSIBs and lung cancer risk. Specifically, higher albumin levels were associated with a reduced risk of adenocarcinoma, while elevated MUFA and lactate levels were linked to an increased risk of squamous cell carcinoma and small cell lung cancers, respectively. These findings underscore the importance of OS in lung cancer pathogenesis and suggest potential biomarkers for early detection and targeted prevention strategies. Further research is needed to explore the clinical relevance of these biomarkers and to investigate the underlying biological mechanisms in more detail.