哺乳动物细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开发基于氧化还原调节策略的靶向治疗具有重要意义。在这项研究中，我们证明紫貂因（一种植物来源的小分子黄酮类化合物）是一种新型 TXNRD1 抑制剂。我们发现紫貂因以时间依赖性方式不可逆地抑制重组 TXNRD1 活性。使用 TXNRD1 突变体和 LC-MS，我们确定紫貂因修饰 TXNRD1 的催化半胱氨酸 (Cys) 残基。在细胞环境中，紫貂因促进活性氧 (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，我们发现紫貂因对 TXNRD1 的药理抑制克服了 A549 顺铂耐药细胞的顺铂耐药性，同时细胞 ROS 水平增加和 p53 表达增强。总而言之，本研究的结果表明，紫貂因是 TXNRD1 的有效小分子抑制剂，突出了在铂耐药癌细胞中抑制 TXNRD1 的治疗潜力。© 2024。作者，获得 Springer Science Business 独家许可Media, LLC，隶属于施普林格自然。

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.© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.