Mechanistic link between eIF4E phosphorylation and viral pathogenesis: Therapeutic insights from a porcine model.

Abstract

Eukaryotic initiation factor 4E (eIF4E), a critical component of the host translational machinery, undergoes dynamic phosphorylation mediated by MNK kinases during viral infection, a process exploited by viruses to facilitate replication. To investigate the therapeutic potential of modulating this pathway, we established a sustained eIF4E hypophosphorylation model through pharmacological inhibition of MNK1/2 via eFT508 (15 mg/kg bw), a selective inhibitor. Oral administration of eFT508 significantly suppressed eIF4E phosphorylation across the piglet intestine and reduced viral replication of porcine epidemic diarrhea virus (PEDV). Furthermore, hypophosphorylation of eIF4E effectively restored antioxidant defenses by regulating the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) induced by arecoline treatment. eFT508 treatment also decreased oxidant levels and the production of proinflammatory cytokines, such as IL-6 and TNF-α, upon viral infection with PEDV. We subsequently conducted screening and functional verification via proteomic analysis, and the results revealed that eIF4E phosphorylation regulates downstream proteins, including inflammatory stress regulatory proteins such as TNFAIP3, and inflammatory factors such as NLRP3. These findings suggest that inhibitors targeting the MNK1/2-eIF4E axis confer tissue homeostasis and protection through coordinated anti-inflammatory and antioxidant effects. This work not only elucidates a druggable host factor in virus pathogenesis but also provides preclinical evidence for repurposing eFT508-class compounds in antiviral therapy and livestock resilience enhancement.