Lin Junzuo, Xu Qian, Zhao Zhengfei
Department of Graduate School, Southwest Medical University, Luzhou, 64600, China.
Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 64600, China.
Discov Oncol. 2025 May 21;16(1):838. doi: 10.1007/s12672-025-02683-0.
Colorectal cancer (CRC) is a global health burden, highlighting the urgent need for the discovery of new biomarkers and therapeutic targets. This study integrates genetic epidemiology methods, such as Mendelian randomization (MR), with GWAS data to predict treatment efficacy and identify novel CRC therapeutic targets.
We utilized cis-eQTL data from the eQTLGen consortium and CRC GWAS data from the IEU Open GWAS database. MR analysis was conducted via the R package TwoSampleMR. Bayesian colocalization analysis was applied to identify shared genetic effects between CRC risk factors and potential therapeutic targets. Phenome-wide association study (PheWAS), protein-protein interaction (PPI) network construction, and enrichment analyses were performed to elucidate the functional profiles of the targets. Molecular docking and dynamics simulations were employed to evaluate the therapeutic potential of the identified targets.
MR analysis identified 60 genes associated with CRC risk. Our analysis identified IKZF1 as a significant therapeutic target through colocalization analysis. The PheWAS results revealed no significant genomic correlations for IKZF1, suggesting its potential as a specific therapeutic target. PPI and enrichment analyses highlighted the role of IKZF1 in epigenetic regulation and transcriptional control. Molecular docking and dynamics simulations confirmed the strong binding affinities of potential drugs with IKZF1.
This study identified IKZF1 as a promising therapeutic target for CRC through MR and colocalization analyses. The target's association with immune modulation and epigenetic mechanisms, supported by molecular docking and dynamics simulations, positions IKZF1 as a key player in advancing precision CRC therapies, warranting further clinical investigation.
结直肠癌（CRC）是一项全球健康负担，凸显了发现新生物标志物和治疗靶点的迫切需求。本研究将孟德尔随机化（MR）等遗传流行病学方法与全基因组关联研究（GWAS）数据相结合，以预测治疗效果并识别新的CRC治疗靶点。
我们利用了eQTLGen联盟的顺式表达数量性状基因座（cis-eQTL）数据和IEU开放GWAS数据库中的CRC GWAS数据。通过R包TwoSampleMR进行MR分析。应用贝叶斯共定位分析来识别CRC风险因素与潜在治疗靶点之间的共享遗传效应。进行全表型关联研究（PheWAS）、蛋白质-蛋白质相互作用（PPI）网络构建和富集分析，以阐明靶点的功能特征。采用分子对接和动力学模拟来评估已识别靶点的治疗潜力。
MR分析确定了60个与CRC风险相关的基因。我们的分析通过共定位分析确定IKZF1为一个重要的治疗靶点。PheWAS结果显示IKZF1没有显著的基因组相关性，表明其作为特定治疗靶点的潜力。PPI和富集分析突出了IKZF1在表观遗传调控和转录控制中的作用。分子对接和动力学模拟证实了潜在药物与IKZF1具有很强的结合亲和力。
本研究通过MR和共定位分析确定IKZF1为CRC的一个有前景的治疗靶点。分子对接和动力学模拟支持该靶点与免疫调节和表观遗传机制的关联，这使IKZF1成为推进CRC精准治疗的关键因素，值得进一步开展临床研究。
