The E3 Ubiquitin Ligase RLIM Safeguards Oligodendrocyte Development and Myelination by Targeting SLC7A11 for Polyubiquitination to Regulate Ferroptotic Resistance
ABSTRACT In the central nervous system, oligodendrocytes (OLs) generate myelin sheaths to support rapid nerve impulse conduction. OL lineage cells, especially oligodendrocyte precursor cells (OPCs), feature high metabolic activity and are exposed to severe oxidative stress, but the protective mechanisms remain poorly understood. Here we show that RLIM, an E3 ubiquitin ligase linked to X‐linked neurodevelopmental disorders, safeguards OL development via ferroptosis resistance. RLIM directly polyubiquitinates SLC7A11, a key cystine/glutamate antiporter for glutathione (GSH) synthesis, thereby sustaining SLC7A11 membrane localization. OL lineage‐specific ablation of RLIM in mice reduces membrane SLC7A11, impairs OPC proliferation, and triggers ferroptosis and thus myelination defects, leading to motor, social, and cognitive deficits that mimic patient phenotypes. Most pathological RLIM missense variants disrupt SLC7A11 binding and/or polyubiquitination. Importantly, GSH supplementation rescues myelination defects and behavioral abnormalities in RLIM‐deficient mice. These findings reveal that the RLIM–SLC7A11‐GSH signaling axis governs ferroptosis resistance in OL lineage cells, implicates this pathway in RLIM‐related neurodevelopmental disorders, and suggests GSH as a potential therapeutic strategy.