From Environmental Lead Exposure to Colorectal Cancer: Integrated Transcriptomic and Genetic Analyses Identify HMOX1 as a Prioritized Candidate.

Colorectal cancer (CRC) is a leading cause of cancer mortality, and the mechanisms linking lead exposure to CRC remain unclear. In this study, we integrated population-level association (NHANES), transcriptomic analyses (bulk and single-cell RNA-seq), and genetic evidence to prioritize candidate genes potentially connecting lead exposure and CRC. In NHANES, higher blood lead levels were associated with increased odds of self-reported CRC in the crude and partially adjusted models, but this association was attenuated and no longer statistically significant after full adjustment. Database-driven prioritization combining network toxicology and machine-learning highlighted several candidate genes (HMOX1, IL1B, NLRP3, BCL2, MAPK3, and ALAD). Single-cell RNA-seq and CellChat analyses indicated that HMOX1 is enriched in monocytes/macrophages and may be involved in immune- and oxidative-stress-related signaling within the CRC microenvironment. Exploratory two-sample MR using whole-blood eQTL as an exposure proxy provided genetic evidence consistent with an association between genetically predicted HMOX1 expression and CRC risk. Molecular docking suggested a plausible binding pose of plumbagin within the HMOX1 pocket. Collectively, these results suggest that the crude epidemiologic association between blood lead and CRC prevalence is sensitive to covariate adjustment and generate testable hypotheses implicating HMOX1 for future experimental validation.