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

Oxidativestress plays a critical role in drug-induced liver injury.In recent years, liquiritigenin (LQ), a natural flavonoid distributedin Glycyrrhizae Radix et Rhizoma (Gan Cao), shows protective effectsagainst oxidative hepatotoxicity. However, the underlying mechanismremains unclear. In this study, we mainly investigated the role ofNRF2, a core transcription factor in oxidative stress, in LQ-inducedhepatoprotection. Our results indicated that the function of LQ toeliminate reactive oxygen species in liver cells was dependent onNRF2 activation. Both a canonical signaling pathway and a non-canonicalsignaling pathway are involved in LQ-induced NRF2 activation. LQ inducedNRF2 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 activationin a KEAP1-C151-independent manner. Totally, our study reveals a novelmolecular mechanism underlying the hepatoprotection of LQ, providinga new insight into the pathogenesis and therapeutic strategy of oxidativeliver injury.