Ruiqin Yao

Remote ischemic postconditioning (RIPC) confers neuroprotection in ischemic stroke partly via promoting angiogenesis and neurogenesis, but its precise molecular mechanisms remain unclear; here, we investigated the role of the secreted guidance protein Netrin‐4 (NTN4) and its upstream regulator hypoxia‐inducible factor 1α (HIF‐1α) in mediating RIPC's reparative effects, using endothelial‐specific Ntn4 knockout (KO) mice subjected to transient middle cerebral artery occlusion (MCAO) and RIPC, alongside in vitro assays with brain microvascular endothelial cells (BMECs) and neural stem cells (NSCs) and molecular interaction analyses, including DNA pull‐down and chromatin immunoprecipitation (ChIP), finding that RIPC significantly upregulated NTN4 expression in the ischemic penumbra of MCAO mice, that endothelial‐specific Ntn4 knockout abolished RIPC's protective effects—impairing neurological recovery, angiogenesis and neurogenesis, which were rescued by recombinant NTN4 administration, that NTN4 promoted BMEC proliferation and tube formation via an integrin β1‐PI3K/AKT pathway while conditioned medium from Ntn4‐overexpressing BMECs enhanced NSC neuronal differentiation through an integrin β1‐MAPK/ERK axis, and that RIPC stabilised HIF‐1α, which directly bound the Ntn4 promoter to drive its transcription, collectively establishing that RIPC orchestrates brain repair by stabilising HIF‐1α to transcriptionally activate endothelial NTN4, which signals through integrin β1 to drive parallel PI3K/AKT and MAPK/ERK pathways for angiogenesis and neurogenesis, highlighting this axis as a key therapeutic target in stroke.

Cerebral palsy (CP), mainly resulting from preterm white matter injury (PWMI), remains a leading neurodevelopmental disorder. While oligodendrocyte precursor cell (OPC) differentiation failure is central to PWMI pathology, the metabolic mechanisms remain unclear. Here, untargeted lipidomic and metabolomic profiling of serum samples from retrospective and prospective cohorts of preterm infants identified a CP‐associated metabolic signature, highlighting phosphatidic acid (PA) as a top candidate that was consistently elevated and showed strong discriminative potential. Increased PA levels were validated in both serum and brains of PWMI mice and in OPCs subjected to oxygen‐glucose deprivation/reoxygenation (OGD/R), where PA impaired OPC differentiation and myelination. Mechanistically, PA interacted with and stabilized the E3 ubiquitin ligase TRIM59, increasing its protein abundance and half‐life without affecting mRNA levels. Elevated TRIM59 promoted proteasomal degradation of the oligodendrocyte lineage transcription factor Olig2, a key regulator of OPC maturation. Inhibition of PA synthesis restored Olig2 expression, improved myelination, and rescued differentiation deficits in PWMI mice. Collectively, this study identifies PA as a potential metabolic risk factor associated with preterm CP and uncovers a PA‐TRIM59‐Olig2 signaling axis linking lipid metabolism to OPC differentiation failure and PWMI.

Perinatal hypoxia–ischemia is a leading cause of preterm white matter injury (PWMI), yet mechanisms underlying oligodendrocyte precursor cells (OPCs) dysfunction remain poorly understood. Here, we identify endothelial‐derived Netrin‐4 ( Ntn4 ) as a critical regulator of OPCs proliferation and differentiation in PWMI. Developmental analysis revealed that Netrin‐4, predominantly expressed in cerebrovascular endothelial cells (ECs), peaks during postnatal myelination and correlates with OPCs marker PDGFR‐ α . Conditional endothelial deletion of Ntn4 in mice impaired spatial memory, induced anxiety‐like behavior, and reduced mature oligodendrocytes, accompanied by disrupted myelin ultrastructure. In a PWMI model, endothelial Ntn4 knockout exacerbated myelination deficits and suppressed OPCs proliferation, while inducible deletion at later stages enhanced OPCs differentiation. Mechanistically, Netrin‐4‐overexpressing ECs elevated ET‐1 secretion, which promoted OPCs proliferation but inhibited differentiation via ET‐1 receptor EDNRB. Our findings reveal that endothelial Netrin‐4 is a dual regulator of OPCs dynamics in PWMI, driving proliferation via ET‐1 while impairing differentiation. Targeting the Netrin‐4/ET‐1 axis restores OPCs maturation, offering a potential strategy to mitigate myelination deficits in PWMI.

Preterm white matter injury (PWMI) is a leading cause of cerebral palsy and chronic neurological disabilities in premature infants. It is characterized by defects in oligodendrocyte precursor cell (OPC) differentiation and dysmyelination. Currently, there are no effective therapeutic strategies available in clinical practice. Lipid homeostasis plays a crucial role in myelin development, yet the function of Lipin1 — a key phosphatidic acid phosphatase involved in phospholipid synthesis — remains unclear. In this study, we identified a significant downregulation of Lipin1 in OPCs from PWMI mice, which impaired OPC differentiation and myelin formation. Conversely, Lipin1 overexpression in these mice promoted OPC maturation and enhanced myelin development. We found evidence that N -acetyltransferase 10 (NAT10) acts as a regulator of Lipin1 expression through RNA pull-down and mass spectrometry. NAT10-mediated N ⁴ -acetylcytidine (ac4C) modification enhanced Lipin1 mRNA stability and translation, and NAT10 knockdown in OPCs impaired myelination, highlighting its crucial role in Lipin1-mediated myelination. Our study revealed that the downregulation of Lipin1 impaired OPC differentiation and myelination in PWMI, with NAT10-mediated ac4C modification playing a critical role in regulating Lipin1 expression. These findings highlight Lipin1 and NAT10 as promising therapeutic targets for treating myelination defects in PWMI, warranting further investigation into their potential in preterm birth–related neurological disorders.