Critical involvement of lysyl oxidase in seizure- induced neuronal damage through ERK-Alox5-dependent ferroptosis and its therapeutic implications

Recent insights collectively suggest the important roles of lysyl oxidase (LysOX) in the path-ological processes of several acute and chronic neurological diseases, but the molecular regulatory mech-anisms remain elusive. Herein, we explore the regulatory role of LysOX in the seizure-induced ferroptotic cell death of neurons. Mechanistically, LysOX promotes ferroptosis-associated lipid peroxidation in neu-rons via activating extracellular regulated protein kinase (ERK)-dependent 5-lipoxygenase (Alox5) signaling. In addition, overexpression of LysOX via adeno-associated viral vector (AAV)-based gene transfer enhances ferroptosis sensitivity and aggravates seizure-induced hippocampal damage. Our studies show that pharmacological inhibition of LysOX with b-aminopropionitrile (BAPN) significantly blocks seizure-induced ferroptosis and thereby alleviates neuronal damage, while the BAPN-associated cardiotoxicity and neurotoxicity could further be reduced through encapsulation with bioresponsive amorphous calcium carbonate-based nanocarriers. These findings unveil a previously unrecognized LysOX-ERK-Alox5 pathway for ferroptosis regulation during seizure-induced neuronal damage. Sup-pressing this pathway may yield therapeutic implications for restoring seizure-induced neuronal injury. 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Recent insights suggest the important roles of lysyl oxidase (LysOX) in various neurological diseases, but the molecular mechanisms are still unclear. This study reveals the regulatory role of LysOX in seizure-induced ferroptotic cell death of neurons and uncovers its association with the ERK-Alox5 pathway.