中国比较医学杂志2026，Vol.36Issue(3)：1-18,18.DOI:10.3969/j.issn.1671-7856.2026.03.001
小窝蛋白通过NCOA4-FTH1途径调控铁稳态减缓MAFLD肝细胞衰老
Caveolin-1 regulates iron homeostasis via the NCOA4-FTH1 pathway and slows hepatocyte senescence in metabolic-associated fatty liver disease mice
摘要
Abstract
Objective To investigate the role of caveolin-1(CAV1)in the progression of metabolic-associated fatty liver disease(MAFLD)and its potential mechanisms of action.Methods We identified differential CAV1 expressions in normal,obese,and non-alcoholic fatty liver disease individuals based on the human database GSE126848.A CAV1-knockout(KO)MAFLD mouse model was established by feeding with a high-fat diet for 16 weeks.CAV1 protein expression in the liver was determined by albumin and CAV1 co-localization,and CAV1 mRNA and protein levels were detected in primary hepatocytes.Lipid deposition and inflammation were assessed by hematoxylin-eosin,Oil Red O,and Nile Red staining.Mitochondrial damage was observed by transmission electron microscopy.Cellular senescence and iron metabolism changes were evaluated by immunohistochemistry for cyclin-dependent kinase inhibitor 1A(P21),dihydroethidium staining,and iron staining.We also constructed hepatocyte senescence models and divided them into blank control(Control),palmitic acid(PA),palmitic acid with CAV1 silencing control group(PA+Con-siRNA),palmitic acid with CAV1-small interfering RNA(PA+CAV1-siRNA),palmitic acid with CAV1 overexpression control group(PA+Con-GV107),palmitic acid with CAV1 overexpression groups(PA+CAV1-GV146),palmitic acid with CAV1 silencing and deferoxamine group(PA+CAV1-siRNA+DFO).Lipid deposition,senescence,and Fe2+levels were analyzed,and the effects of CAV1 on hepatocyte senescence and mitochondrial function were validated by Western blot,quantitative reverse transcription-polymerase chain reaction,and mitochondrial membrane potential detection(JC-1)assays.Results In vivo experiments showed that the compared with WT+HFD group,KO+HFD exacerbated lipid deposition,inflammation,and liver senescence,as evidenced by enhanced lipid staining,increased levels of senescence markers,including histone H2A variant X phosphorylation,cyclin-dependent kinase inhibitor 2A(P16),and P21(all P<0.01),decreased levels of the oxidative stress markers glutathione(P<0.05)and superoxide dismutase(P<0.01),increased reactive oxygen species(ROS)and malondialdehyde(P<0.001),and mitochondrial shrinkage with increased mitochondrial membrane density.CAV1 KO also decreased Fe3+(P<0.01)and increased Fe2+accumulation(P<0.001),associated with the nuclear receptor coactivator 4-ferritin heavy chain 1(NCOA4-FTH1)pathway.Compared with KO+HFD+CSD-CON group,supplementation with the CAV1 scaffolding domain significantly improved the reduction of Fe3+and the accumulation of Fe2+(both P<0.01).Compared with the PA+Con-siRNA group,the PA+CAV1-siRNA group showed accelerated lipid accumulation,mitochondrial damage,and cellular senescence,accompanied by elevated mitochondrial reactive oxygen species(mtROS)levels,Fe2+accumulation,increased NCOA4 expression(P<0.001),and decreased FTH1 expression(P<0.05),while CAV1 overexpression attenuated these effects(P<0.05,P<0.01).Immunofluorescence revealed that CAV1 silencing enhanced NCOA4 and FTH1 co-localization,and this effect was reversed by CAV1 overexpression.Notably,Compared with the PA+CAV1-siRNA group,treatment with deferoxamine(DFO)reduced mtROS levels and ameliorated the senescence induced by CAV1 silencing(all P<0.001).Collectively,these result indicate that CAV1 modulates liver senescence,potentially via the NCOA4-FTH1 pathway.Conclusions CAV1 can inhibit MAFLD hepatocyte senescence,possibly by regulating iron homeostasis via the NCOA4-FTH1 pathway.关键词
代谢相关脂肪性肝病/肝细胞衰老/铁稳态/NCOA4-FTH1通路/小窝蛋白/氧化应激/线粒体损伤Key words
MAFLD/hepatocyte senescence/iron homeostasis/NCOA4-FTH1 pathway/CAV1/oxidative stress/mitochondrial damage分类
医药卫生引用本文复制引用
孙予权,许翰林,耿倩倩,王勇,李玉,吴帅,王星雨,郭宁,胡成穆..小窝蛋白通过NCOA4-FTH1途径调控铁稳态减缓MAFLD肝细胞衰老[J].中国比较医学杂志,2026,36(3):1-18,18.基金项目
国家自然科学基金项目(81970516) （81970516）
安徽省教育厅高校科研项目(2023AH050569). （2023AH050569）
