Hepatic HDAC3 Regulates Systemic Iron Homeostasis and Ferroptosis via the Hippo Signaling Pathway  

作　　者：Hongen Meng Yingying Yu Enjun Xie Qian Wu Xiangju Yin Bin Zhao Junxia Min Fudi Wang 

机构地区：[1]The Second Afiliated Hospital,The First Affiliated Hospital,Institute of Translational Medicine,Scho of Public Health,Zhejiang University School of Medicine,Hangzhou,China [2]institute of Emergency Management,Henan Polytechnic University,Jiaozuo,China [3]MOE Key Laboratory of Biosystems Homeostasis and Protection,Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology,and Innovation Center for Cell Signaling Network,Life Sciences Institute,Zhejiang University,Hangzhou 310058,China.

出　　处：《Research》2024年第3期499-511,共13页研究（英文）

基　　金：the National Natural Science Foundation of China(31930057 and 32330047 to F.W.;31970689 to J.M.;31701034,32171166,and 82030003 to Q.W.);the Natural Science Foundation of Henan Province of China(202300410169 to X.Y.).

摘　　要：Histone deacetylases(HDACs)are epigenetic regulators that play an important role in determining cell fate and maintaining cellular homeostasis.However,whether and how HDACs regulate iron metabolism and ferroptosis(an iron-dependent form of cell death)remain unclear.Here,the putative role of hepatic HDACs in regulating iron metabolism and ferroptosis was investigated using genetic mouse models.Mice lacking Hdac3 expression in the liver(Hdac3-LKO mice)have significantly reduced hepatic Hamp mRNA(encoding the peptide hormone hepcidin)and altered iron homeostasis.Transcription profiling of Hdac3-LKO mice suggests that the Hippo signaling pathway may be downstream of Hdac3.Moreover,using a Hippo pathway inhibitor and overexpressing the transcriptional regulator Yap(Yes-associated protein)significantly reduced Hamp mRNA levels.Using a promoter reporter assay,we then identified 2 Yap-binding repressor sites within the human HAMP promoter region.We also found that inhibiting Hdac3 led to increased translocation of Yap to the nucleus,suggesting activation of Yap.Notably,knock-in mice expressing a constitutively active form of Yap(Yap K342M)phenocopied the altered hepcidin levels observed in Hdac3-LKO mice.Mechanistically,we show that iron-overload-induced ferroptosis underlies the liver injury that develops in Hdac3-LKO mice,and knocking down Yap expression in Hdac3-LKO mice reduces both iron-overload-and ferroptosis-induced liver injury.These results provide compelling evidence supporting the notion that HDAC3 regulates iron homeostasis via the Hippo/Yap pathway and may serve as a target for reducing ferroptosis in iron-overload-related diseases.

关 键 词：HOMEOSTASIS metabolism EXPRESSING 

分 类 号：R575[医药卫生—消化系统]