A New Perspective on Serum Iron's lmpact on Colorectal Adenocarcinoma: Plasma Proteome-Mediated Analysis

Colorectal adenocarcinoma (CRA) is the third most frequently detected cancer and ranks as the second highest contributor to cancer-related deaths worldwide. The relationship between iron and CRA is ambiguous and interactive, especially when considering the heterogenesis of colon adenocarcinoma and rectal adenocarcinoma. This research utilized Mendelian randomization to examine how serum iron levels are linked to colon adenocarcinoma and rectal adenocarcinoma, respectively. Afterward, proteomic data was utilized for mediation analysis. Analysis using magnetic resonance imaging showed that higher levels of iron in the blood were linked to a higher risk of developing colon adenocarcinoma and rectal adenocarcinoma. In proteomic mediation analysis, signal transducer and activator of transcription 1 and interleukin-22 receptor subunit alpha-1 have the highest mediating ratio in 32 proteins involved in colon adenocarcinoma, while neural cell adhesion molecule 1, torsin-1a-interacting protein 2, and polymeric immunoglobulin receptor have the highest mediating ratio in 31 proteins involved in rectal adenocarcinoma. The signaling of interferon-alpha/beta and interleukin-6 were the most relevant pathways in colon adenocarcinoma, and apoptosis pathways were the main pathways involved in rectal adenocarcinoma. Ferroptosis-related proteins such as thioredoxin-interacting protein in colon adenocarcinoma, mitogen-activated protein kinase 1, and calcineurin B homologous protein 1 in rectal adenocarcinoma also served as mediator proteins. Our research clarifies the causal impact of serum iron levels in the development of CRA, emphasizing unique molecular pathways involved in CRA.