Remdesivir(RDV),广谱抗病毒药物,通常与地塞米松(DEX)一起用于需要呼吸支持的住院COVID-19患者。潜在的肝脏药物不良反应是与使用RDV相关的安全性问题。我们先前报道,DEX联合治疗可有效减轻RDV诱导的肝毒性,并降低培养的人原代肝细胞(HPH)和住院COVID-19患者的血清ALT和AST水平升高,分别。然而,这种保护性药物-药物相互作用背后的确切机制仍然未知.我们在这里表明,通过激活p38,c-JunN末端激酶(JNK),和细胞外信号调节激酶1和2(ERK1/2)信号,RDV诱导细胞凋亡(caspases8、9和3的裂解),自噬(自噬体和LC3-II增加),和线粒体损伤(膜电位降低,呼吸,ATP水平,在HPH中Bax和释放的胞浆细胞色素C)的表达增加。重要的是,与DEX共同治疗部分逆转了RDV诱导的细胞凋亡,自噬,细胞死亡。机械上,DEX失活/去磷酸化p38,JNK,和ERK1/2信号通过增强双特异性蛋白磷酸酶1(DUSP1)的表达,丝裂原活化蛋白激酶(MAPK)磷酸酶,以糖皮质激素受体(GR)依赖性方式。HPH中GR的敲低减弱DEX介导的DUSP1诱导,MAPK去磷酸化,以及对RDV诱导的肝毒性的保护。总的来说,我们的研究结果表明,DEX通过调节GR-DUSP1-MAPK调节轴以减轻RDV在肝脏中的不良反应的分子机制.意义声明该研究揭示了地塞米松在COVID-19治疗背景下保护雷米西韦相关肝损伤的分子机制。
Remdesivir (RDV), a broad-spectrum antiviral agent, is often used together with dexamethasone (DEX) for hospitalized COVID-19 patients requiring respiratory support. Potential hepatic adverse drug reaction is a safety concern associated with the use of RDV. We previously reported that DEX cotreatment effectively mitigates RDV-induced hepatotoxicity and reduces elevated serum alanine aminotransferase and aspartate aminotransferase levels in cultured human primary hepatocytes (HPH) and hospitalized COVID-19 patients, respectively. Yet, the precise mechanism behind this protective drug-drug interaction remains largely unknown. Here, we show that through the activation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling, RDV induces apoptosis (cleavage of caspases 8, 9, and 3), autophagy (increased autophagosome and LC3-II), and mitochondrial damages (decreased membrane potential, respiration, ATP levels, and increased expression of Bax and the released cytosolic cytochrome C) in HPH. Importantly, cotreatment with DEX partially reversed RDV-induced apoptosis, autophagy, and cell death. Mechanistically, DEX deactivates/dephosphorylates p38, JNK, and ERK1/2 signaling by enhancing the expression of dual specificity protein phosphatase 1 (DUSP1), a mitogen-activated protein kinase (MAPK) phosphatase, in a glucocorticoid receptor (GR)-dependent manner. Knockdown of GR in HPH attenuates DEX-mediated DUSP1 induction, MAPK dephosphorylation, as well as protection against RDV-induced hepatotoxicity. Collectively, our findings suggest a molecular mechanism by which DEX modulates the GR-DUSP1-MAPK regulatory axis to alleviate the adverse actions of RDV in the liver. SIGNIFICANCE STATEMENT: The research uncovers the molecular mechanisms by which dexamethasone safeguards against remdesivir-associated liver damage in the context of COVID-19 treatment.