Research progress on ferroptosis mediated by ferritinophagy in Alzheimer′s disease

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 <?A3B2 pi129?>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 <?A3B2 pi129?>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 <?A3B2 pi129?>ubiquitin ligase HERC2 (modulating NCOA4 <?A3B2 pi129?>stability) and the iron-responsive element (IRE)-iron regulatory protein (IRP) system (regulating FTH1 <?A3B2 pi129?>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 <?A3B2 pi129?>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. <alternatives id="alt1"> </alternatives>