The ferroptosis-lipid metabolism-neuroinflammation axis in Alzheimer's disease: A review of mechanistic interplay and therapeutic implications

Alzheimer's disease (AD) involves multiple pathological pathways, with ferroptosis and lipid metabolic dysregulation forming a coupled mechanism across the disease course, and neuroinflammation acting as a key mediator. While existing reviews often focus on isolated processes, they frequently lack an integrative analysis of the “ferroptosis–lipid–neuroinflammation axis” as a systemic pathological core. This review specifically addresses this gap by proposing a unified mechanistic framework for neuronal injury, synaptic dysfunction, and immunometabolic remodeling in AD, centered on this tripartite axis. We comprehensively summarize how key pathways involving glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), coenzyme Q10 (CoQ10), the cystine/glutamate antiporter system Xc − , solute carrier family 7 member 11 (SLC7A11), AMP-activated protein kinase (AMPK), nuclear factor erythroid 2-related factor 2 (NRF2), and N6-methyladenosine (m 6 A) regulation shape neuroinflammation within this context. Furthermore, we explore how advanced methodologies, including spatial omics, single-cell transcriptomics, organoid models, and engineered exosome methods, are instrumental in elucidating regional specificity, optimal intervention windows, and targeted delivery strategies for modulating this iron-lipid-inflammation interplay. This axis functions as a pathological amplifier, linking metabolic, oxidative, immune, and structural dysfunctions. Its systemic reprogramming offers a new paradigm for AD subtyping, biomarker discovery, and multitarget interventions, thereby overcoming the limitations of traditional amyloid-β/tau-centric approaches. This review integrates literature published up to the submission date, ensuring the inclusion of the latest mechanistic insights and translational advances in the ferroptosis–lipid metabolism–neuroinflammation axis.