[ Decoction improves liver steatosis by inhibiting hepatocyte ferroptosis in mice with Wilson's disease through the GPX4/ACSL4/ALOX15 signaling pathway].

OBJECTIVES

To explore the mechanism of Decoction (GDFMD) for improving Wilson's disease (WD) in tx-J mice.

METHODS

With 6 syngeneic wild-type mice as the control group, 30 tx-J mice were randomized into WD model group, low-, medium- and high-dose GDFMD treatment groups, and Fer-1 treatment group. Saline (in control and model groups) and GDFMD (3.48, 6.96 or 13.92 g/kg) were administered by gavage, and Fer-1 was injected intraperitoneally once daily for 14 days. Oil red and HE staining were used to observe lipid deposition and pathological conditions in the liver tissue; ALT, AST, albumin, AKP levels were determined to assess liver function of the mice. Western blotting and RT-qPCR were used to detect hepatic protein and mRNA expressions of GPX4, ACSL4, ALOX15, FTH1, FLT, TFR1, FAS, SCD1, and ACOX1, and Fe, MDA, ROS, SOD, GSH and 4-HNE levels were analyzed to assess oxidative stress.

RESULTS

The mouse models of WD showed obvious fatty degeneration in the liver tissue significantly increased serum levels of ALT, AST and AKP, decreased albumin level, increased Fe, MDA, ROS, 4-HNE levels, decreased SOD and GSH levels (<0.05), lowered protein expressions of ACOX1, GPX4, FTH1, FLT, FAS, and SCD1, and increased protein contents of TFR1, ACSL4 and ALOX15 in the liver. Treatment with GDFMD and Fer-1 improved liver histopathology and liver function of the mouse models, decreased the levels of Fe, MDA and ROS, increased SOD and GSH levels, and reversed the changes in hepatic protein expressions.

CONCLUSIONS

GDFMD improves liver steatosis in mouse models of WD possibly by inhibiting hepatocyte ferroptosis through the GPX4/ACSL4/ALOX15 signaling pathway.