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

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.

SUBMITTER: Guo J

PROVIDER: S-EPMC10511756 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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

Guo Jun J Yin Jiameng J Liu Pu P Zhang Xin X Wei Jie J Wang Mingjun M Xiao Yanxia Y Zhen Yongzhan Y Lin Yajun Y Li Jian J

Frontiers in pharmacology 20230906

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 mous ...[more]

PMID: 37745084

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Project description:CD39 or NTPDase1 and other nucleoside triphosphate diphosphohydrolases (NTPDases), including NTPDase2, NTPDase3, and NTPDase8, regulate purinergic signaling through tuning the extracellular levels of purine nucleotides and nucleosides. Purinergic signaling can regulate liver ischemia-reperfusion (I/R) injury and CD39 is protective. However, the role of other NTPDases is unkown. In this study, we have investigated the roles of NTPDase2, NTPDase3, and NTPDase8 in liver I/R injury. Global Entpd2-/-, Entpd3-/-, and Entpd8-/- and control wild-type (WT) mice were subjected to a 60 minutes of warm hepatic ischemia, which was followed by a 6-hour reperfusion period. In addition, WT and Entpd8-/- mice underwent global ischemia induced by hemorrhagic shock and resuscitation. Liver and plasma samples were collected to assess the extent and mechanisms of liver injury. Bone marrow chimeric mice derived from Entpd8-/- and WT were generated to understand the role of NTPDase expression on hematopoietic cells in regulating liver injury. While wild-type (WT), Entpd2-/- and Entpd3-/- mice exhibited comparable levels of liver injury following local IR, Entpd8-/- mice had increased liver injury compared to WT mice. This was evidenced by increased levels of plasma transaminases (ALT and AST) and histological evidence of heightened hepatocellular damage. Studies with bone marrow chimeric mice indicated that NTPDase8 on parenchymal liver cells protected against hepatic injury. This was confirmed by single-nucleus RNAseq showing hepatocytes are the dominant cell type expressing NTPDase8 in the liver. Entpd8-/- mice after I/R injury were noted to have higher ATP concentrations in the liver and plasma. The P2 antagonist suramin decreased plasma ALT and AST levels in Entpd8-/- mice indicating that extracellular ATP-mediated purinergic signaling contributes to liver injury in these mice. Finally, Entpd8-/- mice had increased liver injury compared to WT mice also after global IR induced by hemorrhagic shock and resuscitation.These findings highlight the differential roles of NTPDase family members in the liver, with parenchymal/hepatocyte expression of NTPDase8 emerging as a critical suppressor of the inflammatory and metabolic responses to hepatic ischemia-reperfusion insult, even in the presence of vascular NTPDase1 expression.

Project description:BackgroundFerroptosis is the process of cell death triggered by lipid peroxides, and inhibition of glutathione (GSH) synthesis leads to ferroptosis. Liver cancer progression is closely linked to ferroptosis suppression. However, the mechanism by which inhibition of GSH synthesis suppresses potential ferroptosis of liver cancer cells and whether ferroptosis-related liver cancer biomarkers have a promising diagnostic value remain unknown.MethodsRibonucleotide reductase regulatory subunit M2 (RRM2) levels were measured using an enzyme linked immunosorbent assay (ELISA), quantitative RT-PCR (qPCR), immunoblotting (IB) and immunochemistry (IHC). Cell viability and cell death were measured by a CellTiter-Glo luminescent cell viability assay and staining with SYTOX Green followed by flow cytometry, respectively. Metabolites were measured using the indicated kits. The Interaction between glutathione synthetase (GSS) and RRM2 was measured using immunofluorescence (IF), co-immunoprecipitation (co-IP) and the proximal ligation assay (PLA). The diagnostic value was analyzed using the area under the receiver operating characteristic curve (AUC-ROC). Bioinformatics analysis was performed using the indicated database.ResultsRRM2 showed specifically elevated levels in liver cancer and inhibited ferroptosis by stimulating GSH synthesis via GSS. Mechanistically, phosphorylation of RRM2 at the Threonine 33 residue (T33) was maintained at normal levels to block the RRM2-GSS interaction and therefore protected RRM2 and GSS from further proteasome degradation. However, under ferroptotic stress, RRM2 was dephosphorylated at T33, thus the RRM2-GSS interaction was promoted. This resulted in the translocation of RRM2 and GSS to the proteasome for simultaneous degradation. Clinically, serum RRM2 was significantly associated with serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (?-GT), albumin (ALB) and total bilirubin. The AUC-ROC for the combination of RRM2 with AFP was 0.947, with a sensitivity of 88.7% and a specificity of 97.0%, which indicates better diagnostic performance compared to either RRM2 or AFP alone.ConclusionRRM2 exerts an anti-ferroptotic role in liver cancer cells by sustaining GSH synthesis. Serum RRM2 will be useful as a biomarker to evaluate the degree to which ferroptosis is suppressed and improve diagnostic efficiency for liver cancer.

Dataset Information

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

Publications

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

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