Cisplatin induces acute liver injury by triggering caspase-3/GSDME-me diate d cell pyroptosis  

作　　者：Ping-Ping Wu Xiu-Jin Shen Shu-Sen Zheng 

机构地区：[1]Division of Hepatobiliary Pancreatic Surgery,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China [2]Kidney Disease Center,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China [3]Key Laboratory of Kidney Disease Prevention and Control Technology,Hangzhou 310003,China [4]NHC Key Laboratory of Combined Multi-organ Transplantation,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China

出　　处：《Hepatobiliary & Pancreatic Diseases International》2025年第2期177-187,共11页国际肝胆胰疾病杂志(英文版)

基　　金：supported by grants from the National Natural Science Foundation of China(8170060495 and 82170682)。

摘　　要：Background:Cisplatin triggers Gasdermin E(GSDME)cleavage,causing membrane bubble formation,content release,and inflammation.Caspase-3 activation initiates GSDME cleavage,and thus inhibiting this pathway mitigates cisplatin-induced pyroptosis in hepatocytes.This study aimed to delve into how cisplatin induces liver injury via pyroptosis.Methods:For animal experiments,C57BL/6J mice were divided into three groups:control,liver injury model group,and Ac-DMLD-CMK(caspase-3 inhibitor)intervention group.The liver histology was evaluated by hematoxylin and eosin staining,immunohistochemistry,immunofluorescence and TUNEL staining.The mRNA and protein levels were detected by real-time polymerase chain reaction(PCR)and Western blot analysis.For in vitro experiments,HL-7702 cells were treated with cisplatin or GSDME siRNA.Cell pyroptosis was determined via cellular morphology,cytotoxicity and viability detection,flow cytometric assay,and Western blot detection for the expression of pyroptosis-related proteins.Results:Cisplatin-induced distinct liver morphological changes,hepatocellular injury,and inflammation in mice,along with elevated serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels and increased pro-inflammatory cytokine expression.Heightened macrophage infiltration and hepatocellular death indicated cisplatin-induced hepatotoxicity.Cisplatin upregulated GSDME activation,along with Bax-mediated caspase-3 cleavage both in vivo and in vitro,implicating caspase-3/GSDME-dependent pyroptosis in liver injury.Treatment with Ac-DMLD-CMK ameliorated cisplatin-induced liver injury,reducing hepatocellular lesions,serum ALT and AST levels,cytokine expression,macrophage infiltration,and hepatocyte death.Ac-DMLD-CMK also attenuated GSDME-dependent pyroptosis post-cisplatin induction,as evidenced by decreased GSDME expression,Bax upregulation,and cleaved caspase-3 activation.For HL-7702 cells,GSDME siRNA transfection reduced GSDME expression,attenuated typical signs of cisplatin-induced pyroptosis,partially r

关 键 词：CISPLATIN PYROPTOSIS HEPATOTOXICITY Gasdermins GSDME 

分 类 号：R575[医药卫生—消化系统]