Epigenetic Regulation of Ferroptosis in Central Nervous System Diseases

Ferroptosis, a newly identified form of cell death, is characterized by iron overload and accumulation of lipid reactive oxygen species. Inactivation of pathways, such as glutathione/glutathione peroxidase 4, NAD(P)H/ferroptosis suppressor protein 1/ubiquinone, dihydroorotate dehydrogenase/ubiquinol, or guanosine triphosphate cyclohydrolase-1/6(R)-l-erythro-5,6,7,8-tetrahydrobiopterin pathways, have been found to induce ferroptosis. The accumulating data suggest that epigenetic regulation can determine cell sensitivity to ferroptosis at both the transcriptional and translational levels. While many of the effectors that regulate ferroptosis have been mapped, epigenetic regulation in ferroptosis is not yet fully understood. Neuronal ferroptosis is a driver in several central nervous system (CNS) diseases, such as stroke, Parkinson's disease, traumatic brain injury, and spinal cord injury, and thus, research on how to inhibit neuronal ferroptosis is required to develop novel therapies for these diseases. In this review, we have summarized epigenetic regulation of ferroptosis in these CNS diseases, focusing in particular on DNA methylation, non-coding RNA regulation, and histone modification. Understanding epigenetic regulation in ferroptosis will hasten the development of promising therapeutic strategies in CNS diseases associated with ferroptosis.

Automated summary

Ferroptosis, characterized by iron overload and accumulation of lipid reactive oxygen species, can be induced by inactivation of various pathways. Epigenetic regulation plays a role in determining cell sensitivity to ferroptosis, although it is not fully understood. Neuronal ferroptosis is involved in CNS diseases, and this review focuses on epigenetic regulation of ferroptosis in these diseases, including DNA methylation, non-coding RNA regulation, and histone modification. Understanding epigenetic regulation in ferroptosis will contribute to the development of therapeutic strategies for CNS diseases associated with ferroptosis.