Mori fructus aqueous extracts attenuates liver injury by inhibiting ferroptosis via the Nrf2 pathway

Yuanyuan Wei; Chen Gao; Huiru Wang; Yannan Zhang; Jinhua Gu; Xiuying Zhang; Xuhao Gong; Zhihui Hao

doi:10.1186/s40104-023-00845-0

Mori fructus aqueous extracts attenuates liver injury by inhibiting ferroptosis via the Nrf2 pathway

J Anim Sci Biotechnol. 2023 Apr 10;14(1):56. doi: 10.1186/s40104-023-00845-0.

Authors

Yuanyuan Wei^{1

2

3}, Chen Gao^{1

2

3}, Huiru Wang^{1

2

3}, Yannan Zhang^{1

2

3}, Jinhua Gu^{2

4}, Xiuying Zhang^{2

4}, Xuhao Gong^{2

4}, Zhihui Hao^{5

6

7}

Affiliations

¹ Innovation Centre of Chinese veterinary medicine, College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing, 100193, China.
² Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing, 100193, P. R. China.
³ National Center of Technology Innovation for Medicinal function of Food, National Food and Strategic Reserves Administration, Beijing, China.
⁴ China Institute of Veterinary Drug Control, Beijing, 100081, China.
⁵ Innovation Centre of Chinese veterinary medicine, College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing, 100193, China. haozhihui@cau.edu.cn.
⁶ Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing, 100193, P. R. China. haozhihui@cau.edu.cn.
⁷ National Center of Technology Innovation for Medicinal function of Food, National Food and Strategic Reserves Administration, Beijing, China. haozhihui@cau.edu.cn.

Abstract

Background: Liver fibrosis and hepatocellular carcinogenesis secondary to liver fibrosis are serious liver diseases with no effective treatments. Mori fructus aqueous extracts (MFAEs) have served as successful treatments for many types of liver injury including fibrosis although the molecular mechanisms are unknown at present.

Purpose: To investigate the effect of MFAEs in alleviating acute and chronic liver injury and tried to decipher the underlying mechanism.

Methods and results: Mice were divided into 5 groups (n = 8) for acute (groups: control, 0.3% CCl₄, bifendate (BD), 100 and 200 mg/kg MFAEs, 7 d) and chronic (groups: control, 10% CCl₄, BD, 100 and 200 mg/kg MFAEs, 4 weeks) liver injury study. Each mouse was injected intraperitoneally with 10 µL/g corn oil containing CCl₄ expect the control group. HepG2 cells were used in vitro study. Eighteen communal components were identified by UPLC-LTQ-Orbitrap-MS. We utilized a mouse model for acute and chronic liver injury using CCl₄ and MFAEs administration effectively blocked fibrosis and significantly inhibited inflammation in the liver. MFAEs activated the nuclear factor erythroid derived 2 like 2/heme oxygenase 1 (Nrf2/HO-1) pathway and promoted the synthesis of the antioxidants glutathione (GSH), superoxidedismutase (SOD) and glutathione peroxidase (GSH-Px) that resulted in reduced levels of CCl₄-induced oxidative stress molecules including reactive oxygen species. These extracts administered to mice also inhibited ferroptosis in the liver by regulating the expression of Acyl-CoA synthetase long chain family member 4 (ACSL4), solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), thus reducing the occurrence of liver fibrosis. Both in vivo and in vitro tests indicated that the mechanism of MFAEs protection against liver fibrosis was linked to activation of Nrf2 signaling. These effects were blocked in vitro by the addition of a specific Nrf2 inhibitor.

Conclusion: MFAEs inhibited oxidative stress, ferroptosis and inflammation of the liver by activating Nrf2 signal pathway and provided a significant protective effect against CCl₄-induced liver fibrosis.

Keywords: Acute and chronic liver injury; Ferroptosis; Mori fructus aqueous extracts; Nrf2; Oxidative stress.

Abstract

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