Comprehensive multi-omics analysis elucidates colchicine-induced toxicity mechanisms and unveils the therapeutic potential of MLN4924 and kinase inhibitors  

作　　者：Lin-hui Zhai Xing-long Jia Yu-lu Chen Mu-yin Liu Jing-dan Zhang Shao-jie Ma Xiu-jun Wang Wen-hao Cheng Jing-liang He Jiao-jiao Zhou Ling-yi Zuo Mei-qi Zhang Qing Yuan Meng-han Xu Jing Ji Min-jia Tan Bin Liu 

机构地区：[1]Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening,College of Pharmacy,Jiangsu Ocean University,Lianyungang,222005,China [2]Translational Research Institute of Brain and Brain-like Intelligence,Shanghai Fourth People’s Hospital,School of Medicine,Tongji University,Shanghai,200434,China [3]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [4]School of Pharmacy,Fudan University,Shanghai,201203,China [5]Department of Cardiology,Shanghai Institute of Cardiovascular Diseases,Zhongshan Hospital,Fudan University,Shanghai,200032,China [6]School of Pharmaceutical Sciences,Southern Medical University,Guangzhou,510515,China [7]Zhongshan Institute for Drug Discovery,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Zhongshan,528400,China

出　　处：《Acta Pharmacologica Sinica》2025年第3期702-714,共13页中国药理学报(英文版)

基　　金：supported by grants from the National Natural Science Foundation of China(82273167,22225702,32171434);the Program of Shanghai Academic Research Leader(22XD1420900);the State Key Laboratory of Drug Research(SIMM2105KF-13);Jiangsu Province Basic Research Program Natural Science Foundation(Outstanding Youth Fund Project,BK20220063);the Key Program of Basic Science(Natural Science)of Jiangsu Province(22KJA350001);“Huaguo Mountain Talent Plan”of Lianyungang City(Innovative Talents to Bin Liu).

摘　　要：Colchicine is a widely prescribed anti-inflammatory drug for the treatment of gout,familial Mediterranean fever and pericarditis,but its narrow therapeutic window presents a significant risk of severe toxicity.Despite its clinical relevance,the molecular mechanisms underlying colchicine’s pharmacological effects and associated toxicity and explored potential therapeutic interventions to mitigate its adverse effects.We showed the colchicine’s impact on cellular morphology in human umbilical vein endothelial cells(HUVEC)and HeLa cells including cell rounding and detachment following 24 h of exposure that revealed pronounced cytotoxic effects.We then established a large-scale screening model to identify small molecules capable of reversing colchicine-induced cellular toxicity,and identified MLN4924,an inhibitor of the Cullin-RING E3 ligase(CRL)system,as a promising candidate for mitigating colchicine-induced cellular injury.Through a comprehensive multi-omics approach including transcriptomics,proteomics,phosphoproteomics and ubiquitinomics,we systematically characterized the molecular perturbations caused by colchicine and delineated the protective mechanisms of MLN4924.We found that MLN4924 exerted its protective effects by modulating critical cellular pathways,specifically preventing the dysregulation of cell cycle progression,mitotic disruption and microtubule destabilization triggered by colchicine.Furthermore,proteomic and phosphoproteomic analyses revealed significant alterations in kinase signaling networks,with combined inhibition of CDK1 and PAK1 emerging as an effective strategy to counteract colchicine-induced cellular dysfunction.These results not only provide a detailed molecular characterization of colchicine toxicity but also identify key therapeutic targets,laying the groundwork for the development of targeted interventions to mitigate colchicine-induced adverse effects in clinical practice.

关 键 词：COLCHICINE MLN4924 multi-omics analysis PHOSPHOPROTEOMICS ubiquitinomics kinase inhibitor 

分 类 号：R965[医药卫生—药理学]