Eicosapentaenoic acid attenuates hyperoxia-induced lung injury via p38 MAPK/NF-κB-mediated regulation of glycolytic reprogramming.

Abstract

Despite being a lifesaving intervention for many conditions, supplemental oxygen therapy carries the risk of severe hyperoxia-induced lung injury (HLI). The lack of effective countermeasures drives the urgent need for novel therapeutic strategies and mechanistic research to improve clinical outcomes. Eicosapentaenoic acid (EPA), a marine-derived polyunsaturated fatty acid with anti-inflammatory, antioxidant, and immunomodulatory properties, has exhibited lung-protective effects in experimental models of chronic obstructive pulmonary disease and bronchial asthma, suggesting its potential clinical value. However, its effects on HLI remain unexplored. This study investigated the therapeutic potential of EPA in alleviating HLI and elucidated its underlying mechanisms. We established both cellular and animal models of HLI; using these models, we integrated network pharmacology analysis to evaluate the efficacy of EPA and explore its potential mechanisms of action. Results demonstrated that EPA significantly ameliorated hyperoxia-induced oxidative stress, inflammatory responses, glycolytic reprogramming, and apoptosis in BEAS-2B and MLE-12 cells in vitro. Network pharmacology analysis revealed that EPA likely targets the MAPK/NF-κB signaling pathway. Western blotting and immunofluorescence confirmed that EPA attenuated hyperoxia-induced cellular damage by inhibiting p38 MAPK phosphorylation and reducing NF-κB nuclear translocation. In vivo, EPA suppressed the p38 MAPK/NF-κB signaling pathway, reduced inflammation and metabolic reprogramming in lung tissue, and thereby alleviated hyperoxia-induced pathological damage. This study substantiates that EPA ameliorates HLI by modulating glycolytic reprogramming via the p38 MAPK/NF-κB signaling pathway in vitro and in vivo, thereby providing a potential therapeutic strategy and laying the groundwork for its clinical application in HLI management.