结直肠癌 (CRC) 是全球癌症相关死亡的主要原因之一。增强结直肠癌的诊断和预后需要开发改进的生物标志物和治疗靶点。新的证据表明，未折叠蛋白反应 (UPR) 在 CRC 进展中发挥着关键作用，为诊断、治疗和预防提供了新的机会。本研究假设内质网 (ER) 应激反应基因的遗传变异影响结直肠癌的易感性。我们检查了南伊朗队列中 PERK (rs13045) 和 GRP78/BiP (rs430397) 中 SNP 的频率。我们绘制了结直肠癌中 PERK 和 GRP78 基因的细胞和分子特征，观察它们在肿瘤和转移组织中的差异表达。我们构建了共表达和蛋白质-蛋白质相互作用网络，并进行了基因集富集分析，强调自噬是通过 KEGG 的重要途径。此外，该研究还包括 64 名 CRC 患者和 60 名对照受试者。使用高分辨率熔解 (HRM) 分析进行 DNA 提取和基因分型。在 CRC 组织和对照之间观察到 PERK 和 GRP78 表达的显着差异。 PERK 和 GRP78 基因型的变异与 CRC 风险显着相关。利用多靶点定向配体方法，设计了双重 PERK/GRP78 抑制剂并进行了分子建模研究。对接实验表明所提出的抑制剂与 PERK 和 GRP78 这两个基因之间具有高亲和力结合，这表明了一种新的 CRC 疗法。这些发现强调了了解不同人群的遗传背景对于评估结直肠癌风险的重要性。 UPR 信号通路元件中的多态性可以作为预测 CRC 易感性的潜在标记，为个性化治疗策略铺平道路。版权所有 © 2024。由 Elsevier B.V. 出版。

Colorectal cancer (CRC) ranks among the leading causes of cancer-related deaths worldwide. Enhancing CRC diagnosis and prognosis requires the development of improved biomarkers and therapeutic targets. Emerging evidence suggests that the unfolded protein response (UPR) plays a pivotal role in CRC progression, presenting new opportunities for diagnosis, treatment, and prevention. This study hypothesizes that genetic variants in endoplasmic reticulum (ER) stress response genes influence CRC susceptibility. We examined the frequencies of SNPs in PERK (rs13045) and GRP78/BiP (rs430397) within a South Iranian cohort. We mapped the cellular and molecular features of PERK and GRP78 genes in colorectal cancer, observing their differential expressions in tumor and metastatic tissues. We constructed co-expression and protein-protein interaction networks and performed gene set enrichment analysis, highlighting autophagy as a significant pathway through KEGG. Furthermore, the study included 64 CRC patients and 60 control subjects. DNA extraction and genotyping were conducted using high-resolution melting (HRM) analysis. Significant differences in PERK and GRP78 expressions were observed between CRC tissues and controls. Variations in PERK and GRP78 genotypes were significantly correlated with CRC risk. Utilizing a Multi-Target Directed Ligands approach, a dual PERK/GRP78 inhibitor was designed and subjected to molecular modeling studies. Docking experiments indicated high-affinity binding between the proposed inhibitor and both genes, PERK and GRP78, suggesting a novel therapy for CRC. These findings highlight the importance of understanding genetic backgrounds in different populations to assess CRC risk. Polymorphisms in UPR signaling pathway elements may serve as potential markers for predicting CRC susceptibility, paving the way for personalized therapeutic strategies.Copyright © 2024. Published by Elsevier B.V.