Iron Metabolism and Ferroptosis in Peripheral Nerve Injury

Abstract

Peripheral nerve injury (PNI) is a major clinical problem that may lead to different levels of sensory and motor dysfunction including paralysis. Due to the high disability rate and unsatisfactory prognosis, the exploration and revealment of the mechanisms involved in the PNI are urgently required. Ferroptosis, a recently identified novel form of cell death, is an iron-dependent process. It is a unique modality of cell death, closely associated with iron concentrations, generation of reactive oxygen species, and accumulation of the lipid reactive oxygen species. These processes are regulated by multiple cellular metabolic pathways, including iron overloading, lipid peroxidation, and the glutathione/glutathione peroxidase 4 pathway. Furthermore, ferroptosis is accompanied by morphological changes in the mitochondria, such as increased membrane density and shrunken mitochondria; this association between ferroptosis and mitochondrial damage has been detected in various diseases, including spinal cord injury and PNI. The inhibition of ferroptosis can promote the repair of damaged peripheral nerves, reduce mitochondrial damage, and promote the recovery of neurological function. In this review, we intend to discuss the detailed mechanisms of ferroptosis and summarize the current researches on ferroptosis with respect to nerve injury. This review also aims at providing new insights on targeting ferroptosis for PNI treatment.

Identification and verification of ferroptosis‐related genes in diabetic foot using bioinformatics analysis

“…35 In addition, ferroptosis was found to induce axonal degeneration and impair nerve function in animal models, suggesting its potential role in the development of peripheral neuropathy in DF. 36,37 However, the mechanisms through which ferroptosis contributes to tissue damage and inflammation in DF warrant further elucidation. Therefore, it is necessary to identify ferroptosis-related biomarkers early and explore the underlying pathogenesis of DF to suppress disease aggravation and provide guidance to achieve successful treatment.…”

“…Moreover, ferroptosis may contribute to the development of peripheral neuropathy, a common complication of diabetes that can lead to loss of sensation in the feet, followed by foot ulcers 35 . In addition, ferroptosis was found to induce axonal degeneration and impair nerve function in animal models, suggesting its potential role in the development of peripheral neuropathy in DF 36,37 . However, the mechanisms through which ferroptosis contributes to tissue damage and inflammation in DF warrant further elucidation.…”

Targeting Ferroptosis in Bone-Related Diseases: Facts and Perspectives

“…Fe 3+ is reduced to Fe 2+ by different ferrireductases in the intestine such as duodenal cytochrome B (DCYTB), and then Fe 2+ enters enterocytes via divalent metal transporter 1 (DMT1) on the apical membrane. 10 Ferritin iron and heme iron can enter enterocytes via ferritin receptor and CD91, respectively. 11 In enterocytes, Fe 2+ not involved in biological processes can be bound to ferritin for storage.…”

“… 18 Excess Fe 2+ also promotes lipid peroxidation by participating in the catalytic subunit of lipoxygenase (LOX). 10 , 17 Excess intracellular Fe 2+ can be oxidized to Fe 3+ by ferritin and stored as ferritin heavy chain 1 (FTH1) or ferritin light chain (FTL). 19 This iron-binding ferritin can be degraded by nuclear receptor coactivator 4 (NCOA4) and release free iron.…”

Nerve Guide Conduits Integrated with Fisetin‐Loaded Chitosan Hydrogels for Reducing Oxidative Stress, Inflammation, and Nerve Regeneration

“…Existing literature suggests that peripheral nerve injury (PNI) is a prevalent condition, provoking sensory and motor dysfunction. [1] Major factors such as violence, motor vehicle accidents, and iatrogenic injuries have been identified as the primary causes DOI: 10.1002/mabi.202300476 of PNI, instigating inflammation, fibrosis, scarring, and the release of neurotoxic cytokines at the injury site. [2,3] Surgical intervention has been established as the standard treatment for PNI.…”