Glabridin enhances hepatic tolerance to ischemia/reperfusion stress via PI3K/AKT/Nrf2-associated adaptive responses

Hepatic ischemia/reperfusion injury (HIRI) contributes to liver dysfunction after transplantation and hepatic surgery. Glabridin (Gla), a bioactive isoflavan, has antioxidant and anti-inflammatory properties, but its effects on HIRI remain unclear. Male C57BL/6J mice were pretreated with Gla before induction of hepatic I/R, and AML12 hepatocytes were subjected to hypoxia/reoxygenation. Liver injury, oxidative stress, inflammation, apoptosis, and PI3K/AKT/Nrf2-associated signaling were evaluated. Molecular docking, cellular thermal shift assay, and drug affinity responsive target stability assay were used to examine potential engagement of PIK3R1/p85α. Gla reduced serum transaminase levels and histopathological injury in mice and improved AML12 cell viability after hypoxia/reoxygenation. It also reduced oxidative stress, pro-inflammatory cytokine expression, and apoptosis. These effects were accompanied by increased phosphorylation of PI3K p85 and AKT, nuclear Nrf2 accumulation, and HO-1 expression. LY294002 partially attenuated the signaling and hepatoprotective effects of Gla. Collectively, Gla attenuated hepatic I/R injury, with its protective effects being at least partly associated with PI3K/AKT signaling and Nrf2-related antioxidant adaptation.