Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland (K.L., Z.L., L.L., S.R.W., H.W.); BioIVT, Halethorpe, Maryland (S.H.); and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland (L.H.).
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland (K.L., Z.L., L.L., S.R.W., H.W.); BioIVT, Halethorpe, Maryland (S.H.); and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland (L.H.)
Mol Pharmacol. 2024 Jun 18;106(1):71-82. doi: 10.1124/molpharm.124.000894.
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.
瑞德西韦（RDV）是一种广谱抗病毒药物，常与地塞米松（DEX）联合用于需要呼吸支持的住院 COVID-19 患者。潜在的肝药物不良反应是与 RDV 使用相关的安全问题。我们之前报道过，DEX 共处理可有效减轻 RDV 诱导的肝毒性，并分别降低培养的人原代肝细胞（HPH）和住院 COVID-19 患者中升高的血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平。然而，这种保护性药物相互作用的确切机制在很大程度上仍然未知。在这里，我们表明，RDV 通过激活 p38、c-Jun N 末端激酶（JNK）和细胞外信号调节激酶 1 和 2（ERK1/2）信号通路，诱导 HPH 中的细胞凋亡（半胱天冬酶 8、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 水平降低以及 Bax 表达增加和胞质细胞色素 C 释放）。重要的是，DEX 共处理部分逆转了 RDV 诱导的细胞凋亡、自噬和细胞死亡。从机制上讲，DEX 通过增强糖皮质激素受体（GR）依赖性双特异性蛋白磷酸酶 1（DUSP1）的表达来使 p38、JNK 和 ERK1/2 信号失活/去磷酸化，DUSP1 是一种丝裂原激活蛋白激酶（MAPK）磷酸酶。在 HPH 中敲低 GR 会减弱 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作用。总之，我们的研究结果表明了 DEX 调节 GR-DUSP1-MAPK 调节轴以减轻 COVID-19 治疗中 RDV 相关肝毒性的分子机制。
该研究揭示了地塞米松在 COVID-19 治疗中针对瑞德西韦相关肝损伤的保护作用的分子机制。
