NOX4 exacerbates Parkinson's disease pathology by promoting neuronal ferroptosis and neuroinflammation  

作　　者：Zhihao Lin Changzhou Ying Xiaoli Si Naijia Xue Yi Liu Ran Zheng Ying Chen Jiali Pu Baorong Zhang 

机构地区：[1]Department of Neurology,The Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang Province,China

出　　处：《Neural Regeneration Research》2025年第7期2038-2052,共15页中国神经再生研究（英文版）

基　　金：supported by the National Natural Science Foundation of China,Nos.82271444(to JP),82271268(to BZ),and 82001346(to YL);the National Key Research and Development Program of China,No.2022YFE0210100(to BZ)。

摘　　要：Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.

关 键 词：dopaminergic neuron ferroptosis NADPH oxidase 4(NOX4) NEUROINFLAMMATION Parkinson's disease 

分 类 号：R742.5[医药卫生—神经病学与精神病学]