马兜铃酸靶向CHEK1促进肝细胞癌复发  

Aristolochic acid promotes hepatocellular carcinoma recurrence by targeting CHEK1

作　　者：朱慧霖 宋石盛楠 钱璐[1,2] 易铭逊 戚冯南 张晓璐 谈乐韬 张海健 ZHU Huilin;SONG-SHI Shengnan;QIAN Lu;YI Mingxun;QI Fengnan;ZHANG Xiaolu;TAN Letao;ZHANG Haijian(Research Center of Clinical Medicine,Affiliated Hospital of Nantong University,Jiangsu 226001;Medical School of Nantong University)

机构地区：[1]南通大学附属医院临床医学研究中心,江苏226001 [2]南通大学医学院

出　　处：《南通大学学报(医学版)》2025年第1期1-7,共7页Journal of Nantong University(Medical sciences)

基　　金：国家自然科学基金资助项目(81401988);中国博士后科学基金项目(2019M661907);江苏省博士后科学基金项目(2019K159,2019Z153);江苏省卫健委面上项目(H2023136);南通市卫健委面上项目(MS2023013);江苏省研究型医院项目(YJXYY202204-YSB28);大学生创新项目(202210304128Y,2023103041055,202410304132Y)。

摘　　要：目的:马兜铃酸作为一种已知的潜在肝毒性化合物,其与肝细胞癌的发生及复发之间的关系仍未得到充分阐明,本文意在探讨马兜铃酸促进肝细胞癌复发的可能机制。方法:首先挑选出马兜铃酸的毒性基因、复发性肝细胞癌中上调基因,二者的交集基因聚焦于“有丝分裂细胞周期阶段转换”功能模块,以此模块构建的标签评分能有效预测肝细胞癌复发。随后,运用分子对接技术甄别出与马兜铃酸亲和力最强的核心基因,最后对该基因进行验证。结果:根据所有分子对接结果的热图展示,选取检查点激酶1(checkpoint kinase 1,CHEK1)作为主要的潜在靶点。无论是在发现队列还是验证队列中,CHEK1高表达均促进肝细胞癌复发,CHEK1表达在肝细胞癌复发患者中显著上调,提示其与马兜铃酸结合进一步加重肝细胞癌复发的风险。结论:本研究阐明了马兜铃酸的肝毒性机制及其靶向CHEK1促进肝细胞癌复发的可能机制,提示在抗肿瘤治疗中应严格管理马兜铃酸的暴露,以减少肝细胞癌复发的风险。Objective:Aristolochic acid,as a known potential hepatotoxic compound,has not yet been fully elucidated in its relationship with the occurrence and recurrence of hepatocellular carcinoma.This article aims to explore the possible mechanisms by which aristolochic acid promotes the recurrence of hepatocellular carcinoma.Methods:First,the toxicity genes associated with aristolochic acid and the upregulated genes in recurrent hepatocellular carcinoma were selected.The intersection of these two sets of genes focused on the functional module of“mitotic cell cycle phase transition”.The label score constructed based on this module can effectively predict the recurrence of hepatocellular carcinoma.Subsequently,molecular docking technology was used to identify the core gene with the strongest affinity to aristolochic acid,and finally,this gene was validated.Results:Based on the heatmap presentation of all molecular docking results,checkpoint kinase 1(CHEK1)was selected as the primary potential target.In both the discovery group and validation group,high expression of CHEK1 promoted the recurrence of hepatocellular carcinoma.CHEK1 expression was significantly upregulated in patients with recurrent hepatocellular carcinoma,suggesting that its binding with aristolochic acid further exacerbates the risk of hepatocellular carcinoma recurrence.Conclusion:This study elucidates the hepatotoxic mechanisms of aristolochic acid and its potential role in targeting CHEK1 to promote recurrence of hepatocellular carcinoma,which suggests that aristolochic acid exposure should be strictly controlled during anti-tumor treatment to reduce the risk of hepatocellular carcinoma recurrence.

关 键 词：网络毒理学 马兜铃酸 肝细胞癌复发 分子对接 检查点激酶1 

分 类 号：R735.7[医药卫生—肿瘤]