《生命科学》 2026, 38(5): 870-877
铁自噬介导铁死亡在阿尔茨海默病中的研究进展
摘 要：
铁自噬是一种选择性自噬，通过核受体辅激活因子4（nuclear receptor coactivator 4，NCOA4）将细胞内铁蛋白转移到自噬溶酶体中进行降解并释放出游离铁，以满足多种铁依赖性生理过程的需要。铁自噬作为铁死亡的上游调控机制，其介导的铁死亡在阿尔茨海默病（Alzheimer’s disease，AD）中的重要作用引起广泛关注。故本文对AD的发病机制研究进展进行简单归纳，指出铁自噬和铁死亡在AD中的作用，讨论铁自噬介导的铁死亡在AD发病中的机制及两者之间的关系；在此基础上，对通过铁自噬介导铁死亡防治AD的研究前景进行了展望，以期为今后的研究提供方向。
通讯作者：董贤慧 , Email:dongxianhuitj@126.com
Abstract:
Alzheimer′s disease (AD), the leading age-related neurodegenerative dementia, is defined by cognitive decline, β-amyloid (Aβ) plaques deposit, and neurofibrillary tangles (NFTs) from hyperphosphorylated tau. Despite extensive research, its pathogenesis remains unclear, and no disease-modifying therapies exist. Ferritinophagy, a selective autophagy regulating iron homeostasis via nuclear receptor coactivator 4 (NCOA4)-dependent ferritin degradation, is a key upstream regulator of ferroptosis, an iron-driven programmed cell death caused by lipid peroxidation and reactive oxygen species (ROS) accumulation. Mounting evidence links dysregulated ferritinophagy and ferroptosis to AD’s pathological cascades. This review synthesizes their molecular mechanisms, crosstalk with AD, and therapeutic potential, providing a framework for future research. AD’s core pathologies and hypotheses (Aβ, tau, neuroinflammation, mitochondrial dysfunction) highlight iron imbalance and ferroptosis as critical contributors. Ferroptosis is driven by free Fe2+-catalyzed Fenton reactions, generating ROS and lethal lipid peroxidation. The glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis is central: GPX4 suppresses ferroptosis by reducing lipid peroxides, with natural compounds like icariin-astragaloside IV-puerarin mixture and Bingchang Powder modulating this axis in AD models. Ferritinophagy maintains iron homeostasis physiologically: NCOA4 binds ferritin heavy chain 1 (FTH1), forming a complex degraded via autophagosome-lysosome fusion to release iron. Pathologically, disrupted ferritinophagy causes Fe2+ overload and ferroptosis. Key regulators include E3 ubiquitin ligase HERC2 (modulating NCOA4 stability) and the iron-responsive element (IRE)-iron regulatory protein (IRP) system (regulating FTH1 transcription). In AD, brain iron deposition enhances ferritinophagy, leading to iron overload. Excess iron promotes Aβ overproduction via amyloid precursor protein (APP) processing interference and accelerates tau hyperphosphorylation via glycogen synthase kinase-3β (GSK-3β) activation. Ferroptotic neuronal death exacerbates neuroinflammation, forming a vicious cycle. AD risk factors like APOEε4 (activating PI3K/AKT to alter autophagic flux) and cellular senescence (impairing ferritinophagy) further dysregulate this pathway. Potential therapeutic targets include JWA, transmembrane protein 164 (TMEM164), and ELAVL1. Dysregulated ferritinophagy-mediated ferroptosis is a pivotal AD pathogenic target. Unresolved questions include Aβ/tau's regulatory mechanisms on ferritinophagy, HERC2- FTH1 competitive binding to NCOA4, and NCOA4-CD63-mediated ferritin secretion. Future research should validate these mechanisms using AD models and clinical specimens, develop specific ferritinophagy modulators (small molecules, traditional Chinese medicine), and explore nanocarrier-based targeted delivery. Elucidating crosstalk with other AD pathways and establishing relevant biomarkers will enable combination therapies. Targeting this pathway shows considerable potential for the treatment of Alzheimer's disease and warrants further translational investigation.
Communication Author：DONG Xian-Hui , Email:dongxianhuitj@126.com
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