Our study demonstrated a dissociation between WNK3 protein (upregulated ~3-fold) and mRNA (downregulated except for a transient 24 h rebound) in neonatal HIE, suggesting post-transcriptional regulation. The WNK3 upregulation may contribute to cerebral edema formation and neurological deficits. These findings are correlative; larger, sex-balanced studies incorporating WNK3 inhibition, direct brain water measurements, and integration with hypothermia therapy are warranted to test WNK3 as a therapeutic target in neonatal HIE.