Ferroptosis in Neurodegenerative Diseases: Iron Dysregulation, GPX4/FSP1 Signaling, and Emerging Neuroprotective...

Neurodegenerative Diseases (NDDs), including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD), and Multiple Sclerosis (MS), are increasingly associated with ferroptosis, a regulated irondependent form of cell death characterised by the excessive accumulation of lipid peroxides.

This review examines the molecular underpinnings of ferroptosis, focusing on dysregulation in iron homeostasis, increased vulnerability of polyunsaturated fatty acids in neuronal membranes, and impairment of antioxidant defence systems, particularly the Glutathione-GPX4 and FSP1-CoQ10-NADPH pathways. Relevant literature was critically analysed to explore mechanistic insights and therapeutic implications.

Pathological hallmarks such as amyloid-β, tau, and α-synuclein were found to disrupt iron metabolism, thereby exacerbating oxidative stress and mitochondrial dysfunction across various NDDs. These alterations significantly contribute to neuronal damage and disease progression through ferroptosis-related mechanisms.

Emerging therapeutic strategies, including radical-trapping antioxidants, iron chelators, and nanotechnology-based delivery systems, show potential in targeting ferroptosis. However, challenges in clinical translation persist. Artificial intelligence and personalised medicine approaches may address these issues by enabling patient stratification, biomarker discovery, and optimisation of therapeutic interventions.

Ferroptosis represents a promising therapeutic target for mitigating oxidative and metal-induced neurotoxicity in neurodegenerative disorders. Future research integrating multiomics profiling, longitudinal clinical data, and advanced computational modelling is essential to validate the efficacy of ferroptosis-targeted interventions and facilitate their successful translation into precision neurotherapeutics.