Fragile X (Fra (X)) syndrome is the most frequent cause of inherited mentalretardation, and it is associated with the fragile site at Xq27.3. In 1991, the FMR1(fragile X mental retardation 1) gene was cloned in the vi...Fragile X (Fra (X)) syndrome is the most frequent cause of inherited mentalretardation, and it is associated with the fragile site at Xq27.3. In 1991, the FMR1(fragile X mental retardation 1) gene was cloned in the vicinity of this site. The muationand abnormal expression of FMR1 are the direct causes of Fra(X) syndrome. The展开更多
Metabolic-associated fatty liver disease(MAFLD),which is previously known as non-alcoholic fatty liver disease(NAFLD),represents a major health concern worldwide with limited therapy.Here,we provide evidence that ferr...Metabolic-associated fatty liver disease(MAFLD),which is previously known as non-alcoholic fatty liver disease(NAFLD),represents a major health concern worldwide with limited therapy.Here,we provide evidence that ferroptosis,a novel form of regulated cell death characterized by iron-driven lipid peroxidation,was comprehensively activated in liver tissues from MAFLD patients.The canonical-GPX4(cGPX4),which is the most important negative controller of ferroptosis,is downregulated at protein but not mRNA level.Interestingly,a non-canonical GPX4 transcript-variant is induced(inducible-GPX4,iGPX4)in MAFLD condition.The high fat-fructose/sucrose diet(HFFD)and methionine/choline-deficient diet(MCD)-induced MAFLD pathologies,including hepatocellular ballooning,steatohepatitis andfibrosis,were attenuated and aggravated,respectively,in cGPX4-and iGPX4-knockin mice.cGPX4 and iGPX4 isoforms also displayed opposing effects on oxidative stress and ferroptosis in hepatocytes.Knockdown of iGPX4 by siRNA alleviated lipid stress,ferroptosis and cell injury.Mechanistically,the triggered iGPX4 interacts with cGPX4 to facilitate the transformation of cGPX4 from enzymatic-active monomer to enzymatic-inactive oligomers upon lipid stress,and thus promotes ferroptosis.Co-immunoprecipitation and nano LC–MS/MS analyses confirmed the interaction between iGPX4 and cGPX4.Our results reveal a detrimental role of non-canonical GPX4 isoform in ferroptosis,and indicate selectively targeting iGPX4 may be a promising therapeutic strategy for MAFLD.展开更多
基金Project supported by the State Education Commission and the National Natural Science Foundation of China.
文摘Fragile X (Fra (X)) syndrome is the most frequent cause of inherited mentalretardation, and it is associated with the fragile site at Xq27.3. In 1991, the FMR1(fragile X mental retardation 1) gene was cloned in the vicinity of this site. The muationand abnormal expression of FMR1 are the direct causes of Fra(X) syndrome. The
基金supported by the grants from National Natural Science Foundation of China (82073915, 91849135, 81673485, 81773719, 81973312 and 81971306)National Key Research and Development Project (2018YFA0108301, China)+2 种基金Shanghai Science and Technology Commission Experimental Animal Grants (21XD1424900, 19140904700, 19140904900 and 21S11901200, China)Shanghai Shuguang Program (19SG32, China)Shanghai “Rising Stars of Medical Talent” Youth Development ProgramYouth Medical Talents-Clinical Pharmacist Program [SHWRS(2020)_087, China]
文摘Metabolic-associated fatty liver disease(MAFLD),which is previously known as non-alcoholic fatty liver disease(NAFLD),represents a major health concern worldwide with limited therapy.Here,we provide evidence that ferroptosis,a novel form of regulated cell death characterized by iron-driven lipid peroxidation,was comprehensively activated in liver tissues from MAFLD patients.The canonical-GPX4(cGPX4),which is the most important negative controller of ferroptosis,is downregulated at protein but not mRNA level.Interestingly,a non-canonical GPX4 transcript-variant is induced(inducible-GPX4,iGPX4)in MAFLD condition.The high fat-fructose/sucrose diet(HFFD)and methionine/choline-deficient diet(MCD)-induced MAFLD pathologies,including hepatocellular ballooning,steatohepatitis andfibrosis,were attenuated and aggravated,respectively,in cGPX4-and iGPX4-knockin mice.cGPX4 and iGPX4 isoforms also displayed opposing effects on oxidative stress and ferroptosis in hepatocytes.Knockdown of iGPX4 by siRNA alleviated lipid stress,ferroptosis and cell injury.Mechanistically,the triggered iGPX4 interacts with cGPX4 to facilitate the transformation of cGPX4 from enzymatic-active monomer to enzymatic-inactive oligomers upon lipid stress,and thus promotes ferroptosis.Co-immunoprecipitation and nano LC–MS/MS analyses confirmed the interaction between iGPX4 and cGPX4.Our results reveal a detrimental role of non-canonical GPX4 isoform in ferroptosis,and indicate selectively targeting iGPX4 may be a promising therapeutic strategy for MAFLD.
