Wedelolactone activates the PI3K/AKT/NRF2 and SLC7A11/GPX4 signalling pathways to alleviate oxidative stress and ferroptosis and improve sepsis-induced liver injury

Introduction: Sepsis-induced liver injury (SILI) is a severe complication of sepsis. Wedelolactone (WEL) can be used to treat liver diseases. However, its therapeutic mechanisms and efficacy in SILI remain unclear. To investigate the therapeutic effects of WEL on SILI and its potential mechanisms of action through in vitro and in vivo experiments. Methods: A SILI model based on lipopolysaccharide (LPS), and AML12 cells were treated with different concentrations of WEL, LY294002 and ML385. The SILI model was established by caecal ligation and puncture (CLP). C57BL/6 mice were administered WEL and biphenyl diester for seven consecutive days, and CLP was then performed 1 h later. Blood and liver tissue were collected 24 h later for subsequent analysis. HE staining, liver function index, oxidative stress index, JC-1 staining, transmission electron microscopy, immunofluorescence staining, Western blot, and inflammatory cytokines were used to detect oxidative stress and ferroptosis-related markers. Results: The in vivo experiments showed that WEL treatment reduced the pathological damage of the liver and decreased ALT and AST, MMP and ROS (the product of iron and lipid peroxidation) and inflammatory factors. WEL also decreased hepatocyte viability in vitro. Inhibition of NRF2 can lead to exacerbation of SILI. The expressions of P-PI3K and P-AKT were up-regulated while HO-1, GPX4, NRF2, and SLC7A11 were down-regulated in vitro and in vivo. Conclusions: Ferroptosis and oxidative stress are pivotal in SILI. WEL mitigates SILI by inhibiting ferroptosis and oxidative stress, primarily through the PI3K/AKT/NRF2 and SLC7A11/GPX4 signalling pathways, thus suggesting a promising therapeutic strategy.