Yang Rui, Sun Shibo, Zhang Qiuyu, Liu Haowen, Wang Ling, Meng Yao, Chen Na, Wang Zihan, Liu Haiyan, Ji Fengyun, Dai Yan, He Gaohong, Xu Weiping, Ye Zhiwei, Zhang Jie, Ma Qiang, Xu Jianqiang
Liaoning Key Laboratory of Chemical Additive Synthesis and Separation (CASS), School of Chemical Engineering, Ocean Technology and Life Science (CEOTLS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin, 124221, China.
Shenzhen Key Laboratory of Soft Mechanics & Smart Manufacturing, Department of Mechanics and Aerospace Engineering, Southern University of Science and Technology, Shenzhen, 518055, China.
Biol Trace Elem Res. 2025 Apr;203(4):1949-1960. doi: 10.1007/s12011-024-04331-0. Epub 2024 Aug 14.
Mammalian cytosolic selenoprotein thioredoxin reductase (TXNRD1) is crucial for maintaining the reduced state of cellular thioredoxin 1 (TXN1) and is commonly up-regulated in cancer cells. TXNRD1 has been identified as an effective target in cancer chemotherapy. Discovering novel TXNRD1 inhibitors and elucidating the cellular effects of TXNRD1 inhibition are valuable for developing targeted therapies based on redox regulation strategies. In this study, we demonstrated that butein, a plant-derived small molecule flavonoid, is a novel TXNRD1 inhibitor. We found that butein irreversibly inhibited recombinant TXNRD1 activity in a time-dependent manner. Using TXNRD1 mutant variants and LC-MS, we identified that butein modifies the catalytic cysteine (Cys) residues of TXNRD1. In cellular contexts, butein promoted the accumulation of reactive oxygen species (ROS) and exhibited cytotoxic effects in HeLa cells. Notably, we found that pharmacological inhibition of TXNRD1 by butein overcame the cisplatin resistance of A549 cisplatin-resistant cells, accompanied by increased cellular ROS levels and enhanced expression of p53. Taken together, the results of this study demonstrate that butein is an effective small molecule inhibitor of TXNRD1, highlighting the therapeutic potential of inhibiting TXNRD1 in platinum-resistant cancer cells.
哺乳动物胞质硒蛋白硫氧还蛋白还原酶（TXNRD1）对于维持细胞硫氧还蛋白1（TXN1）的还原状态至关重要，并且在癌细胞中通常上调。TXNRD1已被确定为癌症化疗的有效靶点。发现新型TXNRD1抑制剂并阐明TXNRD1抑制的细胞效应对于基于氧化还原调节策略开发靶向治疗具有重要价值。在本研究中，我们证明了植物源小分子黄酮类化合物白杨素是一种新型TXNRD1抑制剂。我们发现白杨素以时间依赖性方式不可逆地抑制重组TXNRD1活性。使用TXNRD1突变体变体和液相色谱-质谱联用技术，我们确定白杨素修饰TXNRD1的催化半胱氨酸（Cys）残基。在细胞环境中，白杨素促进活性氧（ROS）的积累，并在HeLa细胞中表现出细胞毒性作用。值得注意的是，我们发现白杨素对TXNRD1的药理抑制克服了A549顺铂耐药细胞的顺铂耐药性，同时伴随着细胞ROS水平的升高和p53表达的增强。综上所述，本研究结果表明白杨素是TXNRD1的有效小分子抑制剂，突出了抑制TXNRD1在铂耐药癌细胞中的治疗潜力。
