Redox-sensitive mTOR-eIF4A signaling promotes selective P-glycoprotein translation.
Cells face a temporal gap in oxidative stress adaptation, in which acute insults require rapid protein synthesis before transcriptional responses are fully established. Here, we show that low-dose glucosamine (GlcN) induces a transient intracellular oxidation-sensitive response and activates redox-sensitive PI3K-AKT-mTORC1 signaling, leading to increased P-glycoprotein (P-gp) abundance without a detectable increase in total ABCB1 mRNA. GlcN enhanced 4E-BP1 phosphorylation and produced a modest increase in global polysome loading. Polysome profiling further showed preferential redistribution of ABCB1 mRNA toward actively translating polysome fractions, whereas the distribution and polysome-associated proportion of GAPDH mRNA remained largely unchanged. Pharmacological inhibition of eIF4A with rocaglamide A and genetic depletion of EIF4A1 both attenuated GlcN-induced P-gp upregulation, supporting a functional contribution of eIF4A to this translational response. Analyses of the ABCB1 5'-untranslated region identified an evolutionarily conserved, highly structured G-rich element with G4-like properties in vitro, providing a candidate structural context for the observed eIF4A sensitivity. In paraquat poisoning models, GlcN increased pulmonary P-gp expression, reduced lung paraquat accumulation, and improved survival, whereas these protective effects were markedly weakened in Abcb1a/Abcb1b knockout mice. Together, these findings support a redox-sensitive mTOR-eIF4A signaling pathway that preferentially enhances ABCB1/P-gp translation and contributes to pulmonary detoxification.