Ferroptosis is a recently identified iron-dependent form of nonapoptotic cell death characterized by reactive oxygen species(ROS) generation and lipid peroxidation.Here,we report a novel iron-dependent form of ferropt...Ferroptosis is a recently identified iron-dependent form of nonapoptotic cell death characterized by reactive oxygen species(ROS) generation and lipid peroxidation.Here,we report a novel iron-dependent form of ferroptosis induced by labile iron and investigate the mechanism underlying this process.We find that labile iron-induced ferroptosis is distinct from canonical ferroptosis and is linked to the mitochondrial pathway.Specifically,the mitochondrial calcium uniporter mediates the ferroptosis induced by labile iron.Interestingly,cells undergoing labile iron-induced ferroptosis exhibit cytoplasmic features of oncosis and nuclear features of apoptosis.Furthermore,labile iron-induced ferroptosis involves a unique set of genes.Finally,labile ironinduced ferroptosis was observed in liver subjected to acute iron overload in vivo.Our study reveals a novel form of ferroptosis that may be implicated in diseases caused by acute injury.展开更多
Background and Aims:Tissue inhibitor of metalloproteinase-1(TIMP-1)plays a role in the excessive generation of extracellular matrix in liver fibrosis.This study aimed to explore the pathways through which TIMP-1 contr...Background and Aims:Tissue inhibitor of metalloproteinase-1(TIMP-1)plays a role in the excessive generation of extracellular matrix in liver fibrosis.This study aimed to explore the pathways through which TIMP-1 controls monocyte chemoattractant protein-1(MCP-1)expression and promotes hepatic macrophage recruitment.Methods:Liver fibrosis was triggered through carbon tetrachloride,and an adenoassociated virus containing small interfering RNA targeting TIMP-1(siRNA-TIMP-1)was administered to both rats and mice.We assessed the extent of fibrosis and macrophage recruitment.The molecular mechanisms regulating macrophage recruitment by TIMP-1 were investigated through transwell migration assays,luciferase reporter assays,the use of pharmacological modulators,and an analysis of extracellular vesicles(EVs).Results:siRNA-TIMP-1 alleviated carbon tetrachloride-induced liver fibrosis,reducing macrophage migration and MCP-1 expression.Co-culturing macrophages with hepatic stellate cells(HSCs)post-TIMP-1 downregulation inhibited macrophage migration.In siRNATIMP-1-treated HSCs,microRNA-145(miRNA-145)expression increased,while the expression of Friend leukemia virus integration-1(Fli-1)and MCP-1 was inhibited.Downregulation of Fli-1 led to decreased MCP-1 expression,whereas Fli-1 overexpression increased MCP-1 expression within HSCs.Transfection with miRNA-145 mimics reduced the expression of both Fli-1 and MCP-1,while miRNA-145 inhibitors elevated the expression of both Fli-1 and MCP-1 in HSCs.miRNA-145 bound directly to the 3'-UTR of Fli-1,and mi RNA-145-EN-riched EVs secreted by HSCs after TIMP-1 downregulation influenced macrophage recruitment.Conclusions:TIMP-1 induces Fli-1 expression through miRNA-145,subsequently increasing MCP-1 expression and macrophage recruitment.MiRNA-145-enriched EVs from HSCs can transmit biological information and magnify the function of TIMP-1.展开更多
基金supported by the Beijing Natural Science Foundation (7202034)the National Natural Science Foundation of China (82170614)。
文摘Ferroptosis is a recently identified iron-dependent form of nonapoptotic cell death characterized by reactive oxygen species(ROS) generation and lipid peroxidation.Here,we report a novel iron-dependent form of ferroptosis induced by labile iron and investigate the mechanism underlying this process.We find that labile iron-induced ferroptosis is distinct from canonical ferroptosis and is linked to the mitochondrial pathway.Specifically,the mitochondrial calcium uniporter mediates the ferroptosis induced by labile iron.Interestingly,cells undergoing labile iron-induced ferroptosis exhibit cytoplasmic features of oncosis and nuclear features of apoptosis.Furthermore,labile iron-induced ferroptosis involves a unique set of genes.Finally,labile ironinduced ferroptosis was observed in liver subjected to acute iron overload in vivo.Our study reveals a novel form of ferroptosis that may be implicated in diseases caused by acute injury.
基金supported by a grant from the National Natural Science Foundation of China(grant numbers 81570542 and 82170614)the WBE Liver Fibrosis Foundation(grant number CFHPC2021042).
文摘Background and Aims:Tissue inhibitor of metalloproteinase-1(TIMP-1)plays a role in the excessive generation of extracellular matrix in liver fibrosis.This study aimed to explore the pathways through which TIMP-1 controls monocyte chemoattractant protein-1(MCP-1)expression and promotes hepatic macrophage recruitment.Methods:Liver fibrosis was triggered through carbon tetrachloride,and an adenoassociated virus containing small interfering RNA targeting TIMP-1(siRNA-TIMP-1)was administered to both rats and mice.We assessed the extent of fibrosis and macrophage recruitment.The molecular mechanisms regulating macrophage recruitment by TIMP-1 were investigated through transwell migration assays,luciferase reporter assays,the use of pharmacological modulators,and an analysis of extracellular vesicles(EVs).Results:siRNA-TIMP-1 alleviated carbon tetrachloride-induced liver fibrosis,reducing macrophage migration and MCP-1 expression.Co-culturing macrophages with hepatic stellate cells(HSCs)post-TIMP-1 downregulation inhibited macrophage migration.In siRNATIMP-1-treated HSCs,microRNA-145(miRNA-145)expression increased,while the expression of Friend leukemia virus integration-1(Fli-1)and MCP-1 was inhibited.Downregulation of Fli-1 led to decreased MCP-1 expression,whereas Fli-1 overexpression increased MCP-1 expression within HSCs.Transfection with miRNA-145 mimics reduced the expression of both Fli-1 and MCP-1,while miRNA-145 inhibitors elevated the expression of both Fli-1 and MCP-1 in HSCs.miRNA-145 bound directly to the 3'-UTR of Fli-1,and mi RNA-145-EN-riched EVs secreted by HSCs after TIMP-1 downregulation influenced macrophage recruitment.Conclusions:TIMP-1 induces Fli-1 expression through miRNA-145,subsequently increasing MCP-1 expression and macrophage recruitment.MiRNA-145-enriched EVs from HSCs can transmit biological information and magnify the function of TIMP-1.
