关键词:

"> 滨蒿内酯, NRF2, GPX4, 代谢功能障碍相关脂肪性肝病, 铁死亡

Abstract:

This study aimed to investigate whether scoparone (SCO) ameliorates metabolic dysfunction-associated steatotic liver disease ( MASLD) by activating the nuclear factor erythroid 2-related factor 2 ( NRF2) / glutathione peroxidase 4 (GPX4) pathway to suppress ferroptosis. Fifty-four male mice were randomly divided into a control group (n = 11) and a high-fat diet (HFD)-induced group (n = 43),which were fed a standard diet or a HFD for eight weeks,respectively. Mice from the control group and the HFD-induced group (n = 3 per group) were randomly selected for model verification. After confirming successful model construction,the remaining mice in the HFD-induced group were randomly divided into the MASLD model group,silymarin group (150 mg/ kg),and low-dose,medium-dose,and high-dose SCO groups (50,100,and 150 mg/ kg),with eight mice in each group. All groups received intragastric administration for four consecutive weeks. Meanwhile,a sodium oleate ( NaOA)-induced HepG2 cell steatosis model was established,which was treated with SCO (100 μmol/ L) alone or in combination with the NRF2 inhibitor ML385 for pathway dependency verification. Liver function indicators,hepatic histopathological changes,and lipid accumulation levels were detected;markers related to oxidative stress and ferroptosis were measured;and the expression levels of NRF2,GPX4,solute carrier family 7 member 11 (SLC7A11),heme oxygenase 1 (HO-1),and acyl-CoA synthetase long chain family member 4 (ACSL4) were analyzed by RT-qPCR and Western blot. The results showed that compared with the MASLD model group,the SCO intervention improved liver function indicators,alleviated hepatic steatosis and intracellular lipid deposition,reduced intracellular ferrous ion (Fe^{2 +} ) accumulation,and enhanced antioxidant capacity. Mechanistically, SCO promoted NRF2 nuclear translocation, upregulated the expression of GPX4,SLC7A11,and HO-1,and inhibited ACSL4 transcription. Notably,all protective effects mediated by SCO were reversed by ML385. In conclusion,SCO effectively inhibits ferroptosis and alleviates MASLD-related liver injury by activating the NRF2 / GPX4 pathway,which synergistically enhances antioxidant defense and suppresses the synthesis of ferroptosis-promoting substrates.

Key words:

"> scoparone, NRF2, GPX4, metabolic dysfunction-associated steatotic liver disease, ferroptosis