L-ascorbate Alleviates Chronic Obstructive Pulmonary Disease through the EGF/PI3K/AKT Signaling Axis

Introduction: The molecular mechanism of L-ascorbate (Vitamin C) in the treatment of Chronic Obstructive Pulmonary Disease (COPD) has not been fully explained. In this study, we aimed to explore the potential signaling pathways of L-ascorbate in the treatment of COPD. Methods: The non-targeted metabolomics method was used to analyze the differential metabolites in the blood of healthy subjects and COPD patients. The COPD rat model was established by exposing them to Cigarette Smoke (CS). Network pharmacology, molecular docking, and molecular dynamics simulation analyses were performed to analyze the regulatory pathways of the differential metabolites. Results: A non-targeted metabolomics analysis revealed metabolic disorders and significantly reduced levels of L-ascorbate in COPD patients compared with healthy subjects. The L-ascorbate intervention reduced lung inflammation and histological damage in COPD rat models. Network pharmacology analysis revealed 280 common targets between L-ascorbate (drug) and COPD (disease), of which seven core targets were MMP3, MME, PCNA, GCLC, SOD2, EDN1, and EGF. According to molecular docking prediction, L-ascorbate had the highest affinity with EGF. Molecular dynamics simulation indicated relatively stable EGF and L-ascorbate complexes. The PI3K/AKT signaling pathway was significantly enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analysis. In vivo and in vitro experiments confirmed that L-ascorbate affected COPD by regulating the EGF/PI3K/AKT pathway. Conclusion: In summary, based on network pharmacology and molecular docking analyses, this study revealed that L-ascorbate affects COPD development by regulating the PI3K/AKT signaling pathway through EGF and thus contributes to the understanding and clinical application of L-ascorbate in the treatment of COPD.