Myelin sheaths wrap neuronal axons and are essential for rapid nerve impulse conduction. Their formation depends on the proliferation, differentiation, and maturation of oligodendrocyte precursor cells (OPCs). Because myelination involves massive membrane expansion and high metabolic activity, OPCs face persistent oxidative stress.

In a study published in Advanced Science, a team led by Prof. Mao Bingyu from the Kunming Institute of Zoology (KIZ), in collaboration with Prof. Zhao Shuhua's team at the First Affiliated Hospital of Kunming Medical University, revealed that the E3 ubiquitin ligase RLIM safeguards oligodendrocyte development and myelination by targeting SLC7A11 for polyubiquitination to regulate ferroptotic resistance.

The researchers found that RLIM is highly expressed in OPCs and oligodendrocytes. When RLIM was deleted in the oligodendrocyte lineage, OPC proliferation was suppressed and ferroptosis occurred, leading to reduced oligodendrocyte numbers, insufficient myelination, and deficits in motor coordination, social memory, and learning. Mechanistically, RLIM directly binds the ferroptosis key regulator SLC7A11 and promotes its K63-linked polyubiquitination. This modification does not promote SLC7A11 degradation but instead enhances its interaction with the membrane transport cofactor SPTBN2, maintaining SLC7A11 membrane localization and function.

The researchers showed that RLIM loss led to reduced SLC7A11 membrane localization, decreased cystine uptake and glutathione (GSH) synthesis, and lipid ROS accumulation triggering ferroptosis. Multiple Tonne-Kalscheuer syndrome-associated RLIM missense mutations weakened SLC7A11 binding or ubiquitination capacity. In RLIM conditional knockout mice, GSH supplementation restored OPC proliferation and myelination, improving motor, social, and cognitive deficits. GSH supplementation also promoted oligodendrocyte regeneration and remyelination in an adult demyelination injury model.

This study establishes the RLIM-SLC7A11-GSH signaling axis as a new mechanism regulating ferroptotic resistance in oligodendrocytes and identifies a potential therapeutic target for RLIM-related neurodevelopmental disorders and demyelinating diseases.