Pharmacological Inhibition of Ferroptosis as a Therapeutic Target for Neurodegenerative Diseases and Strokes

Abstract

Emerging evidence suggests that ferroptosis, a unique regulated cell death modality that is morphologically and mechanistically different from other forms of cell death, plays a vital role in the pathophysiological process of neurodegenerative diseases, and strokes. Accumulating evidence supports ferroptosis as a critical factor of neurodegenerative diseases and strokes, and pharmacological inhibition of ferroptosis as a therapeutic target for these diseases. In this review article, the core mechanisms of ferroptosis are overviewed and the roles of ferroptosis in neurodegenerative diseases and strokes are described. Finally, the emerging findings in treating neurodegenerative diseases and strokes through pharmacological inhibition of ferroptosis are described. This review demonstrates that pharmacological inhibition of ferroptosis by bioactive small‐molecule compounds (ferroptosis inhibitors) could be effective for treatments of these diseases, and highlights a potential promising therapeutic avenue that could be used to prevent neurodegenerative diseases and strokes. This review article will shed light on developing novel therapeutic regimens by pharmacological inhibition of ferroptosis to slow down the progression of these diseases in the future.

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

“…Accumulating evidence supports neuronal ferroptosis as a critical factor in traumatic brain injury (TBI), multiple sclerosis (MS), spinal cord injury (SCI), neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and stroke, including spontaneous intracerebral hemorrhage (ICH), acute ischemic stroke (AIS), and subarachnoid hemorrhage (SAH); in addition, pharmacological inhibition of ferroptosis is supported as a therapeutic strategy for these diseases. 19 Emerging evidence has revealed the role of epigenetic modifications and PTMs in regulating ferroptosis in CNS diseases. Below, we summarize the epigenetic modifications and PTMs regulating ferroptosis in CNS diseases (Table 8 and Fig.…”

“… 237 , 239 Accumulating evidence indicates that ferroptosis plays a role in the genesis of PD. 19 , 87 , 240 – 262 However, data revealing the roles of epigenetic regulation of ferroptosis by ncRNAs in PD are limited. Upregulation of the lncRNA NEAT1 was observed in 1-methyl-4-phenylpyridinium (MPP + )-treated SK-N-SH cells.…”

“…Dysregulated ferroptosis is increasingly recognized as a significant contributor to the pathogenesis of diseases, including cancers, 18 nervous system diseases (NSDs), 19 – 23 cardiovascular diseases (CVDs), 24 – 28 liver diseases, 29 , 30 lung diseases, 31 – 34 , and kidney diseases. 35 Recently, ferroptosis has been recognized to play an important role in halting tumor growth.…”

“… 38 , 39 Accumulating studies have shown that pharmacologically modulating ferroptosis may be a therapeutic approach for NSDs, CVDs, liver diseases, lung diseases, and kidney diseases. 19 , 25 , 40 – 45 …”

Hybrid molecules synergistically mitigate ferroptosis and amyloid-associated toxicities in Alzheimer's disease

“…In doing so, it acts as a crucial regulator that prevents Fe-dependent formation of toxic lipid ROS [ 21 ]. In addition to GPX4, other key players in the regulation of Fe 3+ levels and the control of ferroptosis include Ferroptosis Suppressor Protein 1 (FSP1), Ferritin and Ferroportin (FPN) [ 22 , 23 ]. The intricate dynamics of Fe 3+ accumulation, GSH depletion, reduced GPX4 activity and levels, and generation of LOOH predispose cells to ferroptosis.…”