Phosphatidic Acid‐TRIM59‐Olig2 Signaling Couples Metabolic Dysfunction to Myelination Failure in PWMI

ABSTRACT 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.