Liquiritigenin Confers Liver Protection by Enhancing NRF2 Signaling through Both Canonical and Non-canonical Signaling Pathways

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.