Ferroptosis Mechanisms in Neuropathic Pain and Cognitive Impairment

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and depletion of antioxidant defences. In neuropathic pain, aberrant iron accumulation within neurons and glia contributes to oxidative damage, sensitising nociceptive pathways in the dorsal horn and peripheral nerves. Concomitant loss of glutathione peroxidase 4 activity and impaired cystine uptake via system Xc– exacerbate lipid peroxide accumulation, leading to neuronal dysfunction and persistent pain hypersensitivity. In parallel, hippocampal and cortical circuits governing memory and learning are vulnerable to ferroptotic injury; excess iron and reactive oxygen species disrupt synaptic integrity and neurogenesis, manifesting as cognitive deficits. Crosstalk between inflammatory mediators and ferroptotic signalling further amplifies neuronal damage in both pain and cognition. Therapeutic modulation of iron handling, lipid peroxidation inhibitors and activation of endogenous antioxidant pathways such as the Nrf2–Keap1 axis have shown promise in preclinical models. Progress in understanding ferroptosis in these contexts offers a unifying framework for the mechanistic overlap between chronic pain and cognitive impairment and identifies new avenues for intervention.

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Technical terms

Ferroptosis: An iron-dependent regulated cell death characterised by overwhelming lipid peroxidation and loss of plasma-membrane integrity.

Lipid peroxidation: Oxidative degradation of polyunsaturated fatty acids in membranes, yielding reactive aldehydes that promote cell injury.

Glutathione peroxidase 4 (GPX4): A selenoenzyme that reduces lipid hydroperoxides to non-toxic lipid alcohols, crucial for ferroptosis suppression.

System Xc– (SLC7A11): A cystine/glutamate antiporter that supplies cystine for glutathione synthesis, maintaining cellular redox balance.

Nuclear factor erythroid 2-related factor 2 (Nrf2): A transcription factor that upregulates antioxidant and detoxification genes, thereby modulating sensitivity to ferroptotic stimuli.

References

1. Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects. Signal Transduction and Targeted Therapy (2024).
2. Sirtuin 2 Alleviates Chronic Neuropathic Pain by Suppressing Ferroptosis in Rats. Frontiers in Pharmacology (2022).
3. Transcriptome Profiles of IncRNA and mRNA Highlight the Role of Ferroptosis in Chronic Neuropathic Pain With Memory Impairment. Frontiers in Cell and Developmental Biology (2022).
4. Gastrodin Ameliorates Cognitive Dysfunction in Vascular Dementia Rats by Suppressing Ferroptosis via the Regulation of the Nrf2/Keap1-GPx4 Signaling Pathway. Molecules (2022).