Glycyrrhizin arginine salt protects against cisplation-induced acute liver injury by repressing BECN1-mediated ferroptosis

Jun Guo; Jiameng Yin; Pu Liu; Xin Zhang; Jie Wei; Mingjun Wang; Yanxia Xiao; Yongzhan Zhen; Yajun Lin; Jian Li

doi:10.3389/fphar.2023.1219486

Glycyrrhizin arginine salt protects against cisplation-induced acute liver injury by repressing BECN1-mediated ferroptosis

Front Pharmacol. 2023 Sep 6:14:1219486. doi: 10.3389/fphar.2023.1219486. eCollection 2023.

Authors

Jun Guo^#¹, Jiameng Yin^#^{1

2}, Pu Liu¹, Xin Zhang¹, Jie Wei¹, Mingjun Wang³, Yanxia Xiao¹, Yongzhan Zhen², Yajun Lin¹, Jian Li¹

Affiliations

¹ The Key Laboratory of Geriatrics, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
² Hebei Key Laboratory for Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, China.
³ College of Basic Medical Sciences, Capital Medical University, Beijing, China.

^# Contributed equally.

Abstract

The study aimed to investigate the protective effects and biological mechanisms of glycyrrhizin arginine salt (Gly-Arg) against cisplatin (Cis)-induced liver injury. Our data showed that Gly-Arg improved Cis-induced liver injury. Further study showed that BECN1 (beclin1) and LC3-II/LC3-I protein expression was significantly increased in primary hepatocytes and mouse liver tissues after Cis treatment, but Gly-Arg reduced the protein levels of BECN1 and LC3-II/LC3-I in primary hepatocytes and mouse liver tissues. Also, Gly-Arg improved indicators related to Cis-induced ferroptosis. Furthermore, Cis increased colocalization of lysosomal membrane-associated protein 1A (LAMP1) with ferritin heavy chain 1 (FTH1) in primary mouse hepatocytes, while Gly-Arg intervention attenuated this colocalization in primary hepatocytes. More improtantly, Cis enhanced the formation of the BECN1-xCT complex, thus inhibiting solute carrier family 7 member 11 (SLC7A11, xCT) and glutathione peroxidase-4 (GPX4) activity. In contrast, Gly-Arg intervention disrupted the formation of this complex. However, Gly-Arg alleviated Cis-induced liver injury in mice by preventing autophagic death and ferroptosis through the inhibition of BECN1-xCT complex formation.

Keywords: BECN1-xCT complex; cisplatin; ferroptosis; glycyrrhizin arginine salt; liver injury.

Grants and funding

This work is supported by funds from the National High Level Hospital Clinical Research Funding (BJ-2023-123), Beijing Hospital Nova Project (BJ-2020-086) and National Natural Science Foundation of China (82271597).