National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
J Med Chem. 2023 Aug 24;66(16):11324-11334. doi: 10.1021/acs.jmedchem.3c00815. Epub 2023 Aug 3.
Oxidative stress plays a critical role in drug-induced liver injury. In recent years, liquiritigenin (LQ), a natural flavonoid distributed in Glycyrrhizae Radix et Rhizoma (Gan Cao), shows protective effects against oxidative hepatotoxicity. However, the underlying mechanism remains unclear. In this study, we mainly investigated the role of NRF2, a core transcription factor in oxidative stress, in LQ-induced hepatoprotection. Our results indicated that the function of LQ to eliminate reactive oxygen species in liver cells was dependent on NRF2 activation. Both a canonical signaling pathway and a non-canonical signaling pathway are involved in LQ-induced NRF2 activation. LQ induced NRF2 activation in a KEAP1-C151-dependent manner partially. Meanwhile, LQ led to the blockage of autophagic flux and upregulation of p62, which competitively bound with KEAP1 and conferred NRF2 activation in a KEAP1-C151-independent manner. Totally, our study reveals a novel molecular mechanism underlying the hepatoprotection of LQ, providing a new insight into the pathogenesis and therapeutic strategy of oxidative liver injury.
氧化应激在药物性肝损伤中起着关键作用。近年来，甘草中的天然类黄酮甘草素（LQ）对氧化肝毒性具有保护作用。然而，其潜在机制尚不清楚。在这项研究中，我们主要研究了氧化应激核心转录因子 NRF2 在 LQ 诱导的肝保护中的作用。结果表明，LQ 清除肝细胞内活性氧的功能依赖于 NRF2 的激活。经典信号通路和非经典信号通路均参与 LQ 诱导的 NRF2 激活。LQ 诱导 NRF2 的激活部分依赖于 KEAP1-C151。同时，LQ 导致自噬流阻断和 p62 上调，p62 与 KEAP1 竞争结合，并以 KEAP1-C151 非依赖性方式赋予 NRF2 激活。总的来说，本研究揭示了 LQ 肝保护的新分子机制，为氧化肝损伤的发病机制和治疗策略提供了新的见解。
