Ferroptosis and Alzheimer's disease: Neuroimmune crosstalk and pharmacological opportunities.

Abstract

Alzheimer's disease (AD) develops through interacting proteinopathic, metabolic, oxidative, and neuroimmune processes. Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation and failure of antioxidant defense systems. This review examines the bidirectional interface between ferroptosis and neuroinflammation in AD and distinguishes direct AD-related evidence from findings derived from experimental models and broader ferroptosis or inflammatory studies. Iron dyshomeostasis, impaired ferroportin-dependent iron export, lipid peroxidation, and reduced glutathione/GPX4-dependent protection may increase neuronal susceptibility to ferroptotic injury. In turn, oxidized lipids and danger-associated molecular patterns released from damaged neurons may activate microglia and astrocytes, engage inflammasome and complement signaling, and amplify inflammatory responses. Conversely, cytokine signaling, altered iron handling, and immune-cell redox and lipid remodeling may further increase ferroptotic vulnerability. We also compare ferroptosis-related markers and pathways in neurons, microglia, and astrocytes and discuss potential therapeutic approaches targeting iron metabolism, lipid peroxidation, GPX4 activity, system xc - function, NRF2-related antioxidant defense, neuroimmune signaling, and multitarget compounds. Although available evidence supports an association between ferroptosis-related processes and AD pathobiology, no single marker is sufficient to establish ferroptosis in human AD tissue. This limitation currently restricts the diagnostic and therapeutic interpretation of ferroptosis in AD.

Key Findings

• Ferroptosis is an iron-dependent form of regulated cell death implicated in Alzheimer's disease through oxidative stress and neuroimmune interactions.
• Iron dyshomeostasis, lipid peroxidation, and impaired antioxidant defenses such as glutathione/GPX4 increase neuronal susceptibility to ferroptotic injury in AD.
• Neuroinflammation and ferroptosis have a bidirectional relationship where damaged neurons activate microglia and astrocytes, amplifying inflammatory responses and ferroptotic vulnerability.
• Therapeutic strategies targeting iron metabolism, lipid peroxidation, GPX4 activity, system xc-, NRF2-related antioxidant defense, and neuroimmune signaling show potential for AD treatment.
• Current limitations include the lack of a single definitive ferroptosis marker in human AD tissue, restricting diagnostic and therapeutic applications.

Clinical Significance

Citation

Marakhovskaya Yelizaveta A, Churov Alexey V, Arbatsky Mikhail Set al.. Ferroptosis and Alzheimer's disease: Neuroimmune crosstalk and pharmacological opportunities. Brain research. 2026-Aug-21.