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

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.结直肠腺癌（Colorectal adenocarcinoma, CRA）是全球第三大高发恶性肿瘤，同时也是癌症相关死亡的第二大诱因。铁与结直肠腺癌的关联复杂且存在交互效应，尤其在考虑结肠腺癌与直肠腺癌的异质性时，这一特征更为显著。本研究采用孟德尔随机化（Mendelian randomization）分别分析血清铁水平与结肠腺癌、直肠腺癌的关联，随后利用蛋白质组学数据开展中介分析。磁共振成像（magnetic resonance imaging）分析结果显示，血液中铁水平升高与结肠腺癌、直肠腺癌的发病风险增加显著相关。在蛋白质组学中介分析中，在参与结肠腺癌发病过程的32种蛋白里，信号转导与转录激活因子1（signal transducer and activator of transcription 1）及白细胞介素-22受体亚基α-1（interleukin-22 receptor subunit alpha-1）的中介比例最高；而在参与直肠腺癌发病过程的31种蛋白中，神经细胞黏附分子1（neural cell adhesion molecule 1）、扭转蛋白1a相互作用蛋白2（torsin-1a-interacting protein 2）以及多聚免疫球蛋白受体（polymeric immunoglobulin receptor）的中介比例最高。结肠腺癌相关的核心信号通路为干扰素-α/β通路与白细胞介素-6通路，直肠腺癌则主要以凋亡通路为核心参与通路。此外，铁死亡（Ferroptosis）相关蛋白同样发挥了中介蛋白的作用：结肠腺癌中为硫氧还蛋白相互作用蛋白（thioredoxin-interacting protein），直肠腺癌中则为丝裂原活化蛋白激酶1（mitogen-activated protein kinase 1）与钙调神经磷酸酶B同源蛋白1（calcineurin B homologous protein 1）。本研究明确了血清铁水平在结直肠腺癌发生发展中的因果作用，并强调了结直肠腺癌独特的分子通路特征。