Network pharmacology, molecular docking, molecular dynamics and animal experimental validation to investigate the mechanism of hydrocortisone in treating sepsis-induced acute lung injury

Sepsis-induced acute lung injury (SALI) is a critical condition associated with high morbidity and mortality in the intensive care unit. It is often triggered by severe infection, leading to an excessive and dysregulated inflammatory response, disruption of the alveolar-capillary barrier, and progressive respiratory failure. Although hydrocortisone (HC), as a classic glucocorticoid, is widely used in clinical anti-inflammatory therapy, its specific molecular mechanisms in sepsis-induced ALI remain incompletely elucidated. Network pharmacology was employed to identify potential targets and pathways of HC in the treatment of SALI. Molecular docking and molecular dynamics (MD) simulations were used to validate the interactions between HC and core targets. Subsequently, a cecal ligation and puncture (CLP)-induced SALI animal model was established to further verify the most critical targets. Network pharmacology analysis comprehensively identified 170 key targets related to HC treatment in SALI. Gene Ontology (GO) enrichment analysis revealed essential biological processes (BP), cellular components (CC), and molecular functions (MF), including cytokine signaling pathways, response to lipopolysaccharide, regulation of cytokine production, intracellular substance transport, and cellular signaling. KEGG enrichment analysis indicated that lipid metabolism, immune response, inflammatory diseases, and signaling pathways such as PI3K-Akt and HIF-1 play significant roles in SALI. Protein-protein interaction (PPI) network analysis identified eight core targets: RELA, MAPK3, HSP90AA1, TLR2, HIF-1 A, MAPK1, BCL2, and MYC. Molecular docking demonstrated potential binding mechanisms and affinity between HC and these key targets, indicating strong binding potential. MD simulations, including root mean square deviation (RMSD) and radius of gyration (Rg) analyses, further confirmed the stable binding of HC to these targets. Animal experiments additionally validated the significance of the NF-κB/HIF-1α signaling pathway in HC-treated SALI. This study adopted a multifaceted approach to explore the role and mechanisms of HC in SALI, providing a new theoretical foundation for the treatment of SALI.