Severe hepatotoxicity greatly limits the clinical application of the first-line anti-tuberculosis drug isoniazid(INH). Quercetin(Que) has multiple pharmacological properties, and is regarded as a potential protective agent against a variety of organ injuries. However, the exact effect of quercetin on INH-induced hepatotoxicity and the underlying mechanisms are not yet completely understood. In this study, liver injury models were established in rats and L02 cells to reveal the protective effect of Que on INH-induced hepatotoxicity and the relevant mechanism. The in vivo results indicated that Que pretreatment reduced the level of ALT/AST, improved the liver histopathological changes and substantially mitigated apoptosis in rats. In vitro, it evidently relieved INH-induced cell viability loss and apoptosis in L02 cells. Furthermore, the studies on mechanisms elucidated that Que remarkably elevated the expression of SIRT1 and suppressed NLRP3 inflammasome activation. Meanwhile, Que significantly inhibited the level of tumor suppressor P53, Bax, cleaved-cas3 expressionl and increased Bcl-2 expression to reduce apoptosis in vivo and in vitro. However, SIRT1 inhibitor EX527 reversed the suppression of Que on NLRP3 inflammasome activation and the protection of Que on rat liver injury and cell apoptosis. In short, our findings showed that Que exhibited protective effects against INH-induced liver damage via inhibiting the activation of NLRP3 inflammasome and apoptosis in a SIRT-dependent manner.

严重的肝毒性极大地限制了一线抗结核药物异烟肼（INH）的临床应用。槲皮素（Quecetin）具有多种药理特性，被认为是抵抗各种器官损伤的潜在保护剂。但是，槲皮素对INH诱导的肝毒性的确切作用及其潜在机制尚不完全清楚。在这项研究中，建立了大鼠和L02细胞的肝损伤模型，以揭示Que对INH诱导的肝毒性的保护作用及其相关机制。体内结果表明Que预处理降低了ALT / AST的水平，改善了肝脏的组织病理学变化，并大大减轻了大鼠的细胞凋亡。在体外，它明显缓解了INH诱导的L02细胞的细胞活力丧失和凋亡。此外，对机制的研究表明，Que显着提高了SIRT1的表达，并抑制了NLRP3炎性体的激活。同时，Que显着抑制了肿瘤抑制因子P53，Bax的表达，cas3基因的裂解以及增加的Bcl-2表达，从而减少了体内和体外的细胞凋亡。但是，SIRT1抑制剂EX527逆转了Que对NLRP3炎性体激活的抑制作用，以及Que对大鼠肝损伤和细胞凋亡的保护作用。简而言之，我们的发现表明Que通过以SIRT依赖的方式抑制NLRP3炎性小体的激活和细胞凋亡对INH诱导的肝损伤表现出保护作用。Que显着抑制肿瘤抑制因子P53，Bax，cas3裂解的表达并增加Bcl-2的表达，以减少体内和体外的细胞凋亡。但是，SIRT1抑制剂EX527逆转了Que对NLRP3炎性体激活的抑制作用，以及Que对大鼠肝损伤和细胞凋亡的保护作用。简而言之，我们的发现表明Que通过以SIRT依赖的方式抑制NLRP3炎性小体的激活和细胞凋亡对INH诱导的肝损伤表现出保护作用。Que显着抑制肿瘤抑制因子P53，Bax，cas3裂解的表达并增加Bcl-2的表达，以减少体内和体外的细胞凋亡。但是，SIRT1抑制剂EX527逆转了Que对NLRP3炎性体激活的抑制作用，以及Que对大鼠肝损伤和细胞凋亡的保护作用。简而言之，我们的发现表明Que通过以SIRT依赖的方式抑制NLRP3炎性小体的激活和细胞凋亡对INH诱导的肝损伤表现出保护作用。