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

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

  • Stem Cell Reports. 2026 Apr 14;21(4):102853. doi: 10.1016/j.stemcr.2026.102853.
Xinyu Li 1,  Xiaoyu Yao 2,  Chunjie Guo 2,  Yilin Liu 2,  Meiting Liu 2,  Jing Li 3,  Meng Zhang 4,  Yu Feng 5,  Chao Ren 6,  Ruiqin Yao 7
Affiliations

Affiliations

  • 1 Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu Province 221004, China; Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province 221000, China.
  • 2 Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu Province 221004, China.
  • 3 Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu Province 225000, China.
  • 4 Department of Urology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province 221000, China.
  • 5 Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province 221000, China. Electronic address: [email protected].
  • 6 Department of Neurology, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong Province 264000, China; Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong Province 264000, China; Yantai Municipal Key Medical and Health Laboratory of Yantai Yuhuangding Hospital (Interdisciplinary Brain Science and Geriatric Health Laboratory), Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong Province 264000, China. Electronic address: [email protected].
  • 7 Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu Province 221004, China. Electronic address: [email protected].
PMID: 41825445 DOI: 10.1016/j.stemcr.2026.102853
Abstract

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.

Keywords

HDAC2; Lipin1; SREBP1; hypoxia-ischemia; mTORC1 signaling; myelination; oligodendrocyte precursor cells; preterm white matter injury; sphingolipid biosynthesis.

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