Targeting Ferroptosis in Neurodegenerative Diseases: Therapeutic Potential and Mechanistic Insights of Traditional Chinese Medicine.

Abstract

Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are characterized by progressive and irreversible neuronal loss, whereas current treatments remain largely symptomatic. Ferroptosis is an iron-dependent form of regulated cell death whose execution is defined by iron-enabled phospholipid peroxidation and failure of cellular ferroptosis-defense systems. Mitochondrial metabolism can modify ferroptosis susceptibility, but its contribution varies with cell type and initiating stimulus. Converging evidence implicates ferroptosis in multiple NDs, in which affected regions commonly show iron accumulation, glutathione depletion, and increased lipid peroxidation. With their multi-component and multi-target properties, traditional Chinese medicine (TCM) interventions may modulate several nodes in this network. This review summarizes the core execution and defense mechanisms of ferroptosis, evaluates their roles in major NDs, and critically appraises bioactive herbal compounds, compound formulas, acupuncture, electroacupuncture, and moxibustion. The reported interventions mainly engage the Nrf2/GPX4 antioxidant axis, TFR1/FPN1/FTH1/NCOA4-mediated iron handling, ACSL4-dependent lipid peroxidation, and GPX4-independent defense systems. Because most studies are preclinical and many infer ferroptosis from non-specific markers, the evidence is graded here as direct, supportive, indirect, mixed, or complementary. Translation will require standardized formulations, causal ferroptosis validation, pharmacokinetic and brain-exposure data, validated human biomarkers, and rigorously designed clinical trials.