Sepsis is a common complication of infections that significantly impacts the survival of critically patients. Currently, effective pharmacological treatment strategies are lacking. Auranofin, known as an inhibitor of Thioredoxin reductase (TrxR), exhibits anti-inflammatory activity, but its role in sepsis is not well understood. Here, we demonstrate the significant inhibitory effect of Auranofin on sepsis in a cecal ligation and puncture (CLP) mouse model. In vitro, Auranofin inhibits pyroptosis triggered by Caspase-11 activation. Further investigations reveal that inhibiting TrxR1 suppresses macrophage pyroptosis induced by E. coli, while TrxR2 does not exhibit this effect. TrxR1, functioning as a reductase, regulates the oxidative-reductive status of Thioredoxin-1 (Trx-1). Mechanistically, the modulation of Trx-1's reductive activity by TrxR1 may be involved in Caspase-11 activation-induced pyroptosis. Additionally, inhibiting TrxR1 maintains Trx-1 in its oxidized state. The oxidized form of Trx-1 interacts with Caveolin-1 (CAV1), regulating outer membrane vesicle (OMV) internalization. In summary, our study suggests that inhibiting TrxR1 suppresses OMV internalization by maintaining the oxidized form of Trx-1, thereby restricting Caspase-11 activation and alleviating sepsis.

中文翻译：

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TrxR1 通过调节 Trx-1 的氧化还原状态参与 Caspase-11 的激活。


脓毒症是一种常见的感染并发症，严重影响危重患者的生存。目前，缺乏有效的药物治疗策略。金诺芬被称为硫氧还蛋白还原酶 (TrxR) 抑制剂，具有抗炎活性，但其在脓毒症中的作用尚不清楚。在这里，我们在盲肠结扎穿刺 (CLP) 小鼠模型中证明了金诺芬对脓毒症的显着抑制作用。在体外，Auranofin 抑制由 Caspase-11 激活引发的细胞焦亡。进一步的研究表明，抑制 TrxR1 可以抑制大肠杆菌诱导的巨噬细胞焦亡，而 TrxR2 则不表现出这种作用。 TrxR1 作为还原酶发挥作用，调节硫氧还蛋白-1 (Trx-1) 的氧化还原状态。从机制上讲，TrxR1 对 Trx-1 还原活性的调节可能参与 Caspase-11 激活诱导的细胞焦亡。此外，抑制 TrxR1 可使 Trx-1 保持氧化状态。 Trx-1 的氧化形式与 Caveolin-1 (CAV1) 相互作用，调节外膜囊泡 (OMV) 内化。总之，我们的研究表明，抑制 TrxR1 通过维持 Trx-1 的氧化形式来抑制 OMV 内化，从而限制 Caspase-11 激活并缓解脓毒症。