Mechanism of glycyrrhizin on ferroptosis during acute liver failure by inhibiting oxidative stress

Abstract

The present study aimed to investigate the anti-ferroptosis effects of the HMGB1 inhibitor glycyrrhizin (GLY). The present study used a cell and animal model of acute liver failure (ALF), induced using tumor necrosis factor-α, lipopolysaccharide and D-galactosamine, to investigate the effects of GLY. The expression of glutathione peroxidase 4 (GPX4) and high mobility group protein B1 (HMGB1), heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) were detected were detected by western blotting in L02 hepatocytes and mouse liver. The expression of GPX4 and HMGB1 in L02 hepatocytes and mouse liver was detected by immunofluorescence. The pathological changes to liver tissues were determined by hematoxylin and eosin staining. The levels of lactate dehydrogenase (LDH), Fe2+, reactive oxygen species (ROS) and glutathione (GSH) were tested using kits. Compared with the normal group, the degree of liver damage and liver function in the model animal group was severe. The protein levels of HMGB1 in L02 cells and liver tissues were significantly increased. The expression of NRF2, HO-1 and GPX4 was significantly decreased. The levels of LDH, Fe2+, malondialdehyde (MDA) and ROS were increased, whereas the level of GSH was decreased. Treatment with GLY reduced the degree of liver damage, the expression of HMGB1 was decreased, and the levels of Nrf2, HO-1 and GPX4 were increased. The levels of LDH, Fe2+, MDA, ROS were decreased, while the level of GSH was increased by GLY treatment. The results of the present study indicated that HMGB1 is involved in the process of ferroptosis. The HMGB1 inhibitor GLY significantly reduced the degree of ferroptosis during ALF by inhibiting oxidative stress.

The emerging role of ferroptosis in non-cancer liver diseases: hype or increasing hope?

“…Oxidative stress may underline the pathophysiological correlation between acute liver failure and ferroptosis, as the accumulation of ROS culminates in ferroptosis execution 57 . In lipopolysaccharide (LPS) and D-galactosamine (GalN)-induced ALF mice, the protein levels of GPx4, NRF2, and heme oxygenase-1 (HO-1) were significantly decreased, whereas the level of high mobility group protein B1 (HMGB1) was increased 16 . Moreover, the levels of LDH, Fe 2+ , malondialdehyde (MDA) and ROS were increased, while the level of GSH was decreased.…”

“…Dysregulation of ferroptosis is observed in a wide range of pathological conditions, including chronic pulmonary obstructive disease, intracerebral hemorrhage, degenerative diseases, acute kidney injury, and cancer 2,[9][10][11][12] . Accumulating evidence has addressed that blockage of ferroptosis can mitigate the development and progression of a number of liver diseases, including hemochromatosis, immune-mediated hepatitis, alcoholic steatohepatitis, and acute liver failure ( Fig.2 and Table 1) [13][14][15][16] . Nonetheless, in some circumstance, induction of ferroptosis may be beneficial for adjusting drug resistance and contributing to combined treatment regimens against hepatocellular carcinoma (HCC) [17][18][19] .…”

“…Accumulating evidence has addressed that blockage of ferroptosis can mitigate the development and progression of a number of liver diseases, including hemochromatosis, immune-mediated hepatitis, alcoholic steatohepatitis, and acute liver failure (Fig. 2 and Table 1 ) 13 – 16 . Nonetheless, in some circumstance, induction of ferroptosis may be beneficial for adjusting drug resistance and contributing to combined treatment regimens against hepatocellular carcinoma (HCC) 17 – 19 .…”

“… Disease Ref. Model Compound/target Effect Mechanism/phenotype Acute liver failure 16 LPS/GalN-induced mice L02 cells Glycyrrhizin Inhibition of ferroptosis NRF2, HO-1, and GPx4↑ HMGB1↓ 58 LPS/GalN-induced mice Promethazine Inhibition of ferroptosis NA Acute liver injury 60 PHZ-induced mice/Ad-Sesn2 infected mice HepG2 cells Sestrin2 Inhibition of ferroptosis NRF2, TFR1, ferroportin↑ Alcoholic liver disease 15 SIRT1iKO mice Intestinal sirtuin1 (deficiency) Inhibition of ferroptosis Pro-inflammatory molecules LCN2, SAA1↓ Redox active iron–sulfur CISD1/2↓ 65 Lpin1 -Tg mice Adipose-specific lipin-1 (overexpression) Induction of ferroptosis Adiponectin-sirtuin1, adiponectin-FGF15 axis↓ NF-κB↑ NAFLD 74 CDE diet/MLKL −/− mice Trolox/DFO Inhibition of ferroptosis TNF-α, IL-1β, IL-6↓ Immune-mediated hepatitis 14 ConA-induced/Cav-1 −/− mice Caveolin-1 Inhibition of ferroptosis RNS, iNOS↓ 83 ConA-induced/IDO1 −/− mice IDO1 (deficiency) Inhibition of ferroptosis xCT↑ RNS↓ Ischemia/reperfusion injury 100 I/R mice Liproxstatin-1 Inhibition of ferroptosis MPO↓ 104 HID-fed I/R mice Ferrostatin-1/DFO/α-Tocopherol Inhibition of ferroptosis PTGS2↓ Inflammator...…”

Matrine Can Inhibit the Growth of Colorectal Cancer Cells by Inducing Ferroptosis

“…Therefore, MDA production serves as an index for membrane lipid peroxidation, which indirectly reflects the antioxidant capacity of cells, as well as the degree of damage to cells. 19 In order to confirm the effect of matrine on the antioxidant capacity of HTC116 cells, we estimated the levels of GSH and MDA. In comparison to the control group, GSH levels significantly decreased in the drug intervention group, while MDA levels significantly increased (P < 0.01).…”