Triggering ferroptosis in neurodegenerative diseases

Neuronal death is a defining feature of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and motor neuron diseases, and is accordingly a priority drug target. Among the various cell death pathways, ferroptosis, a form of regulated necrosis driven by iron-dependent lipid peroxidation, has emerged as a prominent candidate underlying neurodegeneration. Despite its potential significance, putative triggers initiating lipid peroxidation cascades that lead to ferroptosis in neurodegenerative diseases remain poorly characterized. This poses significant challenges for developing targeted and disease-specific therapies. We review evidence of ferroptosis in neurodegenerative diseases and examine potential disease-relevant triggers of ferroptosis. We propose that ferroptosis, rather than being initiated by a single triggering event, emerges due to a cumulative erosion of anti-ferroptosis defense systems. This process is likely driven by context-dependent interplay between common hallmarks of neurodegenerative diseases, including neuroinflammation, protein aggregation, mitochondrial dysfunction, altered lipid metabolism, and iron accumulation.