Inflammatory factors and risk of lung adenocarcinoma: a Mendelian randomization study mediated by blood metabolites

Abstract

Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer, and its pathogenesis remains not fully elucidated. Inflammation and metabolic dysregulation are considered to play crucial roles in LUAD development, but their causal relationships and specific mechanisms remain unclear.

Methods: This study employed a two-sample Mendelian randomization (MR) approach to systematically evaluate the causal associations between 91 circulating inflammatory factors, 1,400 serum metabolites, and LUAD. We utilized LUAD genome-wide association studies (GWAS) data from the FinnGen biobank and GWAS data of metabolites and inflammatory factors from the GWAS catalog to conduct two-sample MR analyses. For the identified key metabolites, we further used mediator MR to investigate their mediating effects in the influence of IL-17A on LUAD and explored potential mechanisms through protein-protein interaction and functional enrichment analyses.

Results: The MR analyses revealed that IL-17A (OR 0.78, 95%CI 0.62-0.99) was negatively associated with LUAD, while 71 metabolites were significantly associated with LUAD. Among them, ferulic acid 4-sulfate may play a crucial mediating role in the suppression of LUAD by IL-17A (OR 0.87, 95%CI 0.78-0.97). IL-17A may exert its anti-LUAD effects through extensive interactions with genes related to ferulic acid 4-sulfate metabolism (such as SULT1A1, CYP1A1, etc.), inhibiting oxidative stress and inflammatory responses, as well as downstream tumor-related pathways of ferulic acid 4-sulfate (such as MAPK, NF-κB, etc.).

Conclusion: This study discovered causal associations between IL-17A, multiple serum metabolites, and LUAD occurrence, revealing the key role of inflammatory and metabolic dysregulation in LUAD pathogenesis. Our findings provide new evidence-based medical support for specific inflammatory factors and metabolites as early predictive and risk assessment biomarkers for LUAD, offering important clues for subsequent mechanistic studies and precision medicine applications.

Keywords: blood metabolites; causal inference; inflammatory factors; lung adenocarcinoma; mediation analysis; mendelian randomization.

Figure 1

MR Analysis Process Flowchart.

Figure 2

Forest map of MR results of IL-7A and LUAD.

Figure 3

Forest plot of MR analysis for metabolites meeting inclusion criteria and LUAD risk.

Figure 4

Forest plot of MR analysis for metabolites with strong evidence and LUAD risk.

Figure 5

Forest plot of MR analysis for metabolites with very strong evidence and LUAD risk.

Figure 6

Forest plot of MR analysis for the causal effect of IL-17A on metabolites.

Figure 7

Regulatory network and functional enrichment analysis of IL-17A on Ferulic acid 4-sulfate-related genes. (A) PPI network of IL-17A and Ferulic acid 4-sulfate-related genes. (B) GO functional enrichment bubble plot of Ferulic acid 4-sulfate-related genes. (C) KEGG pathway enrichment bar plot of Ferulic acid 4-sulfate-related genes.