Nuclear Lipin1 recruits HDAC2 to epigenetically repress SREBP1-dependent lipid synthesis and myelination in hypoxic preterm white matter injury.

Preterm white matter injury (PWMI) causes lasting neurological deficits by blocking oligodendrocyte precursor cell (OPC) differentiation. Perinatal hypoxia suppresses mechanistic target of rapamycin complex 1 (mTORC1), essential for OPC maturation. We identify Lipin1 nuclear translocation as a key downstream event of mTORC1 suppression. In PWMI mice, Lipin1 was enriched in OPC nuclei, while primary OPCs and OLN-93 cells showed that mTORC1 inhibition induces Lipin1 dephosphorylation, nuclear accumulation, and impaired differentiation. Mechanistically, nuclear Lipin1 recruits histone deacetylase 2 (HDAC2) to sterol regulatory element-binding protein 1 (SREBP1) target promoters, repressing sphingolipid biosynthesis required for myelination. Lipin1 or HDAC2 knockdown restored SREBP1 targets and OPC differentiation under rapamycin. In vivo, Lipin1 knockdown or HDAC2 inhibition enhanced myelin gene expression, promoted oligodendrocyte maturation, improved myelin ultrastructure, and alleviated motor deficits. Thus, a Lipin1-HDAC2 epigenetic axis mediates hypoxia-induced myelin gene repression, offering targets for white matter repair in preterm infants.