Neonatal hypoxic–ischemic encephalopathy (HIE), a central nervous system disorder caused by oxygen deprivation and reduced cerebral blood flow, involves complex mechanisms including mitochondrial oxidative stress and neuronal injury. The Rab-like GTPase domain-containing protein Aagab has been linked to neuronal regulation by modulating neural precursor cell expressed, developmentally down-regulated protein 4-1 (NEDD4-1)–mediated ubiquitination and degradation of Src homology 2 domain–containing inositol 5-phosphatase 2 (SHIP2). In this study, we investigated the contribution of the Aagab–NEDD4-1–SHIP2 axis to hypoxic-ischemic encephalopathy (HIE) and its influence on mitochondrial oxidative stress. Multi-omics analyses of publicly available RNA sequencing and proteomic datasets from HIE and control rat brain tissues identified SHIP2 as a significantly upregulated gene strongly associated with oxidative stress pathways. In an oxygen–glucose deprivation (OGD) neuronal model, lentiviral knockdown of SHIP2 enhanced neuronal viability, reduced reactive oxygen species production, and restored mitochondrial membrane potential. In vivo, tail-vein delivery of lentiviral vectors to silence SHIP2 in neonatal rat HIE models led to marked improvements in neurological outcomes, including reduced escape latency in the Morris water maze, increased success rates in the ladder-rung test, and diminished brain lesion area. Mechanistic assays demonstrated that Aagab overexpression increased NEDD4-1 levels, promoted SHIP2 ubiquitination, and accelerated its degradation, whereas NEDD4-1 knockdown reversed these effects. Collectively, these findings indicate that Aagab facilitates NEDD4-1–mediated SHIP2 ubiquitination and degradation, thereby alleviating mitochondrial oxidative stress and mitigating HIE-associated neuronal injury. The Aagab–NEDD4-1–SHIP2 regulatory axis may represent a promising molecular target for therapeutic intervention in HIE.
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