Mediation Mendelian randomization study of plasma proteomics reveals the causal relationship and potential mechanisms between iron and colorectal adenocarcinoma

Colorectal adenocarcinoma (CRA) is the third most frequently detected cancer worldwide. The relationship between iron and CRA is ambiguous and interactive, especially when considering the heterogenesis of colon and rectal adenocarcinoma. This research utilized Mendelian randomization to examine how serum iron levels are linked to colon and rectal adenocarcinoma, respectively. Furthermore, proteomic data-based mediation analysis was followed by enrichment analysis to explore mediating pathways. Analysis using magnetic resonance imaging showed that higher levels of iron in the blood were linked to a higher risk of developing colon and rectal adenocarcinoma. In proteomic mediation analysis, signal transducer and activator of transcription 1 (STAT1) and interleukin-22 receptor subunit alpha-1 (IL-22RA1) show the highest mediating ratios among 32 proteins associated with colon adenocarcinoma. In contrast, neural cell adhesion molecule 1 (NCAM1), torsin-1a-interacting protein 2 (TOR1AIP2), and polymeric immunoglobulin receptor (PIGR) exhibit the highest mediating ratios among 31 proteins linked to rectal adenocarcinoma. The signaling of interferon-alpha/beta and interleukin-6(IL-6) were the most relevant pathways in colon adenocarcinoma. The apoptosis pathways were the main pathways involved in rectal adenocarcinoma. Our research clarifies the causal impact of serum iron levels in the development of CRA, emphasizing unique molecular pathways involved in CRA.