Abstract / Summary
Abstract Background Severe pneumonia is a leading cause of ICU admission and mortality worldwide. Uncontrolled host inflammatory responses, rather than pathogens, are the core mechanism driving ARDS and multiple organ failure. Current therapies lack agents combining potent antibacterial activity with safe anti-inflammatory effects. Biapenem, a carbapenem with excellent pulmonary penetration, has shown immunomodulatory activity, but its direct effects on the TLR4/NF-κB/PI3K-AKT axis and concentration-dependent characteristics remain unclear. Methods Network pharmacology and molecular docking identified key targets of biapenem in severe pneumonia. LPS-stimulated A549 cells were treated with low, medium, and high biapenem concentrations; dexamethasone served as positive control. Western blot detected TLR4, AKT, p-AKT, P65, and p-P65; q-PCR measured TLR4, NF-κB p65, AKT1, IL-1β, IL-6, and TNF-α mRNA; ELISA quantified the three inflammatory cytokines in supernatant. Results Network pharmacology identified 78 intersecting targets between biapenem and severe pneumonia, with key targets including AKT1, EGFR, PPARG, JAK2, KIT, PTPN11, ACE, PLG, and SYK. Molecular docking confirmed stable biapenem-AKT1 binding. LPS stimulation elevated TLR4, p-AKT, p-AKT/AKT ratio, and p-P65, while total AKT remained unchanged. Biapenem suppressed p-P65 phosphorylation, dually blocked NF-κB and PI3K/AKT pathways, and downregulated TLR4, thereby extinguishing inflammatory signaling. q-PCR, Western blot, and ELISA results were highly consistent. Conclusion Biapenem exerts anti-inflammatory effects in LPS-stimulated A549 alveolar epithelial cells by inhibiting the TLR4/NF-κB/PI3K-AKT signaling axis. This study establishes the molecular basis for the dual functionality of biapenem, encompassing both anti-infective and anti-inflammatory properties, thereby providing a novel therapeutic strategy for inflammatory diseases such as severe pneumonia.