@article{APS11209,
author = {Lin-hui Zhai and Xing-long Jia and Yu-lu Chen and Mu-yin Liu and Jing-dan Zhang and Shao-jie Ma and Xiu-jun Wang and Wen-hao Cheng and Jing-liang He and Jiao-jiao Zhou and Ling-yi Zuo and Mei-qi Zhang and Qing Yuan and Meng-han Xu and Jing Ji and Min-jia Tan and Bin Liu},
title = {Comprehensive multi-omics analysis elucidates colchicine-induced toxicity mechanisms and unveils the therapeutic potential of MLN4924 and kinase inhibitors},
journal = {Acta Pharmacologica Sinica},
volume = {46},
number = {3},
year = {2025},
keywords = {},
abstract = {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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/11209}
}