This is a review by professors Bush and Ayton. The new way of thinking is "cumulative erosion of anti-ferroptosis defense systems".

Review

Trends Neurosci

. 2025 Jul 21:S0166-2236(25)00138-9.

doi: 10.1016/j.tins.2025.06.008. Online ahead of print.

Triggering ferroptosis in neurodegenerative diseases

Triet P M Nguyen ¹, Francesca Alves ², Darius J R Lane ², Ashley I Bush ³, Scott Ayton ⁴

Affiliations Expand

• PMID: 40695640

DOI: 10.1016/j.tins.2025.06.008

Abstract

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.

The paper is not free, but they made a free Highlights:

Ferroptosis is emerging as a central player in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS).The induction and propagation of ferroptosis stem from the failure of lipid peroxidation defense systems.Validated biomarkers of ferroptosis in neurodegenerative diseases are currently lacking. However, ferroptosis can be inferred based on accumulation of iron, excessive lipid peroxidation, and reduced glutathione levels.Although pathophysiologically relevant triggers of ferroptosis remain elusive, emerging evidence suggests that ferroptosis is orchestrated by a context-dependent and synergistic interactions between the pathological hallmarks of neurodegenerative diseases, including neuroinflammation, protein aggregation, mitochondrial dysfunction, altered lipid metabolism, and iron accumulation.

The future partner of ATH and ATH itself has a lot of work, not only in MSA and PD, but also in AD, ALS, and MS. Does 434 have any value in controlling "cumulative erosion of anti-ferroptosis defense systems" ???. If it has, 434 would become a prevention drug.