Stage-specific CHI3L1/YKL-40 signaling controls generation of oligodendrocyte precursor cells through IL13Rα2-mediated ferroptosis

Oligodendrocyte precursor cells (OPCs) are essential for sustaining myelin plasticity and maintaining oligodendroglial homeostasis throughout life. However, the intrinsic signaling mechanisms that regulate OPC generation from neural progenitors remain incompletely understood. Here, we identify chitinase-3-like protein 1 (CHI3L1/YKL-40) as a stage-specific, intrinsic signaling regulator of oligodendroglial lineage progression. Using human iPSC-derived models, we show that CHI3L1 selectively targets a transient IL13Rα2-expressing pre-OPC population, where it induces ferroptosis through suppression of GPX4, thereby limiting OPC generation. In contrast, CHI3L1 does not trigger cell death in established OPCs but instead suppresses their proliferation and differentiation while promoting a reactive, immune-like transcriptional state. Mechanistically, IL13Rα2 mediates CHI3L1-dependent ferroptotic vulnerability at the pre-OPC stage, distinguishing it from parallel signaling pathways that regulate neuronal differentiation. Functionally, this dual-stage regulation constrains the production and maintenance of OPCs, a critical determinant of oligodendroglial homeostasis and myelin plasticity. These findings define an intrinsic signaling axis that couples stage-specific cell fate vulnerability to ferroptotic cell death, thereby controlling OPC pool dynamics with broad implications for cognitive function and disorders involving disrupted myelination.