Role of MAPK1 in the mechanisms of white matter damage with neonatal ischemic-hypoxic encephalopathy network

Background: This study investigates the network mechanisms underlying white matter injury (WMI) in neonatal hypoxic-ischemic encephalopathy (HIE) through a combination of network pharmacology and experimental validation. Methods: Venn analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, protein-protein interaction (PPI) network construction, hub gene screening, and molecular validation were performed alongside animal experiments to elucidate the mechanisms of WMI in neonatal HIE. Results: A total of 209 intersecting genes were identified for neonatal HIE, WMI, and hypoxic-ischemic brain damage. GO analysis revealed that the primary biological process involved regulating cell communication, with synapses as the main cellular component and identical protein binding as the key molecular function. KEGG pathway analysis highlighted the significance of the neurodegeneration-multiple diseases pathway. PPI analysis identified ten hub genes at the HIE-WMI intersection: NF-KB1, MAPK1, TRAF6, IL-6, AKT, MAPK3, PIK3CA, TNF, MAPK14, and VEGFA. Notably, a literature review of these genes linked inflammatory factors to HIE but revealed no prior reports on the involvement of the MAPK1 family in this disease. Compared with the sham group, experimental validation demonstrated that the mRNA expression of MAPK1 was downregulated in the HIE model. Conclusions: MAPK1 plays a pivotal role in the pathogenesis of WMI in neonatal HIE.