Elevated expression of thioredoxin reductase (TrxR) is associated with the tumorigenesis and resistance to cancer chemoradiotherapy, highlighting the potential of TrxR inhibitors as anticancer drugs. Deoxyelephantopin (DET) is the major active ingredient of Elephantopus scaber and reveals potent anticancer activity. However, the potential mechanism of action and the cellular target of DET are still unknown. Here, we found that DET primarily targets the Sec residue of TrxR and irreversibly prohibits enzyme activity. Suppression of TrxR by DET leads to accumulation of reactive oxygen species and dysregulation in intracellular redox balance, eventually inducing cancer cell apoptosis mediated by oxidative stress. Noticeably, down-regulation of TrxR1 by shRNA increases cell sensitivity to DET. Collectively, targeting of TrxR1 by DET uncovers a novel mechanism of action in DET and deepens the understanding of developing DET as a potential chemotherapeutic agent for treating cancers.

硫氧还蛋白还原酶 (TrxR) 的表达升高与肿瘤发生和对癌症放化疗的抗性有关，突出了 TrxR 抑制剂作为抗癌药物的潜力。Deoxyelephantopin (DET) 是象鲀的主要活性成分并显示出有效的抗癌活性。然而，DET 的潜在作用机制和细胞靶点仍然未知。在这里，我们发现 DET 主要针对 TrxR 的 Sec 残基并不可逆转地抑制酶活性。DET 对 TrxR 的抑制导致活性氧的积累和细胞内氧化还原平衡的失调，最终诱导氧化应激介导的癌细胞凋亡。值得注意的是，shRNA 对 TrxR1 的下调增加了细胞对 DET 的敏感性。总的来说，DET 靶向 TrxR1 揭示了 DET 中的一种新作用机制，并加深了对将 DET 开发为治疗癌症的潜在化学治疗剂的理解。