The Chemical Biology of Ferroptosis in the Central Nervous System

Abstract

Over the past five decades, thanatology has come to include the study of how individual cells in our bodies die appropriately and inappropriately in response to physiological and pathological stimuli. Morphological and biochemical criteria have been painstakingly established to create clarity around definitions of distinct types of cell death and mechanisms for their activation. Among these, ferroptosis has emerged as a unique, oxidative stress-induced cell death pathway with implications for diseases as diverse as traumatic brain injury, hemorrhagic stroke, Alzheimer's disease, cancer, renal ischemia, and heat stress in plants. In this review, I highlight some of the formative studies that fostered its recognition in the nervous system and describe how chemical biological tools have been essential in defining events necessary for its execution. Finally, I discuss emerging opportunities for antiferroptotic agents as therapeutic agents in neurological diseases.

Keywords: ATF4; Chac1; Erk signaling; HIF prolyl hydroxylases; N-acetylcysteine; Nrf-2; Trib3; adaptaquin; c-Myc; cystine transport; ferroptosis; glutathione; glutathione peroxidase-4; iron; mithramycin; reactive lipid species; transglutaminase.