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.

Aberrant Mitochondrial Metabolism in Alzheimer's Disease Links Energy Stress with Ferroptosis.

Alzheimer's disease (AD) is defined by β-amyloid plaques and tau-containing neurofibrillary tangles, but the ensuing cellular derangements that culminate in neurodegeneration remain elusive. Here, a mechanistic link between two AD pathophysiological hallmarks: energy insufficiency and oxidative stress is revealed. It is demonstrated that mitochondrial function and glutathione (GSH) flux are coupled, impacting neuronal ferroptosis susceptibility.

In defence of ferroptosis.

Rampant phospholipid peroxidation initiated by iron causes ferroptosis unless this is restrained by cellular defences. Ferroptosis is increasingly implicated in a host of diseases, and unlike other cell death programs the physiological initiation of ferroptosis is conceived to occur not by an endogenous executioner, but by the withdrawal of cellular guardians that otherwise constantly oppose ferroptosis induction. Here, we profile key ferroptotic defence strategies including iron regulation, phospholipid modulation and enzymes and metabolite systems: glutathione reductase (GR), Ferroptosis suppressor protein 1 (FSP1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), Dihydrofolate reductase (DHFR), retinal reductases and retinal dehydrogenases (RDH) and thioredoxin reductases (TR).

Ferroptosis - a potential feature underlying neratinib-induced colonic epithelial injury.

Purpose: Neratinib, a small-molecule tyrosine kinase inhibitor (TKI) that irreversibly binds to human epidermal growth factor receptors 1, 2 and 4 (HER1/2/4), is an approved extended adjuvant therapy for patients with HER2-amplified or -overexpressed (HER2-positive) breast cancers. Patients receiving neratinib may experience mild-to-severe symptoms of gut toxicity including abdominal pain and diarrhoea. Despite being a highly prevalent complication in gut health, the biological processes underlying neratinib-induced gut injury, especially in the colon, remains unclear.