Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases

Abstract

This article provides an overview of the background knowledge of ferroptosis in the nervous system, as well as the key role of nuclear factor E2-related factor 2 (Nrf2) in regulating ferroptosis. The article takes Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) as the starting point to explore the close association between Nrf2 and ferroptosis, which is of clear and significant importance for understanding the mechanism of neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links ferroptosis to the pathogenesis of NDs. As the disease progresses, damage to the antioxidant system, excessive OS, and altered Nrf2 expression levels, especially the inhibition of ferroptosis by lipid peroxidation inhibitors and adaptive enhancement of Nrf2 signaling, demonstrate the potential clinical significance of Nrf2 in detecting and identifying ferroptosis, as well as targeted therapy for neuronal loss and mitochondrial dysfunction. These findings provide new insights and possibilities for the treatment and prevention of NDs.

Ferroptosis and HMGB2 induced calreticulin translocation required for immunogenic cell death are controlled by the nuclear exporter XPO1

“…Inhibition of XPO1-mediated oxaliplatin-induced HMGB nuclear export increases HCT116 decreases cell death t has been reported previously that cytosolic HMGB1 and HMGB2 can regulate apoptosis through the activation of NF-kB 30,31 and down regulation of Nrf2 32,33 , suggesting that inhibition of HMGB1 and HMGB2 secretion from the nucleus might ameliorate the oxaliplatin-mediated increase in cell death of HCT116 by preventing the down-regulation of Nrf2, a master controller of both ROS and lipid hydroperoxide detoxi cation pathways 32,33 required to prevent ferroptosis 34 . Inhibition of the nuclear exporter XPO1 with 75 nM Selinexor, did indeed signi cantly reduce oxaliplatin-mediated HMGB1 (Fig.…”

“…This offers a potential therapeutic approach to preventing ferroptotic cell death in cardiovascular 31 and pulmonary diseases 64 as well as neurodegenerative diseases 33 such as Friedreich ataxia 65 . Intriguingly, inhibition of HMGB1 secretion 66 and ferroptosis 35 could also potentially prevent the progression of Alzheimer disease, where these pathways are thought to play important roles 33 . These data suggest that both HMGB1 and HMGB2 are mediators of ferroptosis; whereas HMGB2 alone can initiate CRT translocation (Fig.…”

“…Inhibition of HMGB1 and HMGB2 secretion and/or preventing their activation of the NF-kB pathway 30,31 , could potentially prevent ferroptotic cell death in vascular smooth muscle cells 31 and neurons 35 in vivo. This offers a potential therapeutic approach to preventing ferroptotic cell death in cardiovascular 31 and pulmonary diseases 64 as well as neurodegenerative diseases 33 such as Friedreich ataxia 65 . Intriguingly, inhibition of HMGB1 secretion 66 and ferroptosis 35 could also potentially prevent the progression of Alzheimer disease, where these pathways are thought to play important roles 33 .…”