Exploring the role of ferroptosis pathways in Huntington's disease: Insight of pathophysiology to emerging treatment

Abstract

Huntington's disease (HD) is a persistent ailment identified by progressive physical disability, cognitive impairment, and severe psychiatric symptoms. A mutation in the HTT gene is at the root of HD, causing the development of a protein known as mutant huntingtin (mHTT), which wreaks havoc on neuronal health. While oxidative stress and altered iron metabolism have long been associated with HD, new research has shown a novel and intriguing mechanism: ferroptosis. This sort of regulated cell death is caused by iron-dependent lipid peroxidation and evidence suggests that it plays an important role in HD's severe neurodegeneration. mHTT exacerbates oxidative damage and promotes ferroptosis by disrupting iron homeostasis and antioxidant defenses. HD models and patient tissues exhibit enhanced lipid peroxidation, iron overload, and evidence of ferroptotic cell death, indicating ferroptosis as a major contribution to disease pathophysiology. Even more promising is that blocking ferroptosis can save neurons and enhance outcomes in preclinical HD models. This discovery provides a tantalizing view into prospective medicines that could halt or reduce disease development, a dream long sought by patients and families. As our understanding of ferroptosis grows, so does the chance to design novel treatments that target this lethal form of cell death. Exploring the relationship between iron dysregulation, oxidative damage and neurodegeneration in HD may reshape our strategy for combating this tragic disease, offering up new pathways for revolutionary therapeutics.