Med20 regulates myelination in the peripheral nervous system by modulating ferroptosis of Schwann cells

Myelin sheath is essential for the maintenance of neural system functions. The mediator complex (MED) is associated with neurodegenerative diseases. Mutation of the MED subunit Med20 leads to abnormal brain development, but whether Med20 modulates myelination remains unknown. In this study, we report that Med20 is an important modulator of myelination in the peripheral nervous system. Loss of Med20 in Schwann cells (SCs) induces ferroptosis, thus impairing myelination. The functions of Med20 in SCs are mediated by its downstream target DDB1. DDB1 controls SC ferroptosis by regulating Hmox1 through a “ DDB1-UHRF1-BACH1-Hmox1 ” transcription regulation axis and its direct interaction and subsequent simultaneous ubiquitination of the HO-1 protein. HO-1 inhibitor ZnPP or ferroptosis inhibitor Fer-1 is sufficient and efficient for antagonizing ferroptosis in SCs and restoring myelination in Med20 -deficient mice. The results of our study reveal that Med20 is an important regulator in the network that controls myelination in the peripheral nervous system.