Hypoxia modulates senescence, but their physiological link remains unclear. Here, we found that eIF4E2, a hypoxia-activated translation initiation factor, interacted with GSK3β to maintain phosphorylation of p53, thus resisting senescence under hypoxia. RNA-binding protein RBM38 interacted with eIF4E to inhibit the translation of p53, but GSK3β-mediated Ser195 phosphorylation disrupted the RBM38-eIF4E interaction. Through investigation of RBM38 phosphorylation, we found that the eIF4E2-GSK3β pathway specifically regulated proline-directed serine/threonine phosphorylation (S/T-P). Importantly, peptides e2-I or G3-I that blocking eIF4E2-GSK3β interaction can inhibit the basal S/T-P phosphorylation of p53 at multiple sites, therby inducing senescence through transcriptional inhibition. Additionally, a nanobody was screened via the domain where eIF4E2 bound to GSK3β, and this nanobody inhibited S/T-P phosphorylation to promote senescence. Furthermore, hypoxia inhibited eIF4E2-GSK3β pathway by mediating S-Nitrosylation of GSK3β. Blocking eIF4E2-GSK3β interaction promoted liver senescence under hypoxia, thus leading to liver fibrosis, eventually accelerating N, N-diethylnitrosamine (DEN)-induced tumorigenesis. Interestingly, eIF4E2 isoforms with GSK3β-binding motif exclusively exist in mammals, which protect zebrafish heart against hypoxia. Together, this study reveals a mammalian eIF4E2-GSK3β pathway that prevents senescence by maintaining basal S/T-P phosphorylation of p53, which underlies hypoxia adaptation of tissues.