Mechanism of Berberine Ameliorating Severe Pneumonia by Targeting PTGS2 Inhibition to Regulate C‐Type Lectin Receptor Pathway, Mitochondrial Function and Cellular Focalization

Severe pneumonia remains a major global health burden owing to its high morbidity and mortality, placing substantial strain on healthcare systems. Although berberine shows therapeutic potential against lung infections, its effects and mechanisms in severe pneumonia are not fully defined. This study investigated how berberine ameliorates severe pneumonia by regulating the C-type lectin receptor (CLR) pathway, mitochondrial function, and cellular pyroptosis via inhibition of prostaglandin endoperoxide synthase 2 (PTGS2). Network pharmacology and bioinformatics were used to predict downstream targets of berberine for molecular docking and enrichment analysis. A severe pneumonia rat model and a cellular infection model were established, comprising a control group, a Klebsiella pneumoniae infection group, and berberine treatment groups at different doses. Hematoxylin-eosin staining, enzyme-linked immunosorbent assay, immunohistochemistry, and TUNEL staining were performed to evaluate lung pathology, inflammatory cytokines, expression and localization of related proteins, apoptosis, and pyroptosis. Docking indicated tight binding of berberine to PTGS2 and modulation of multiple inflammation-related pathways. In vivo, berberine improved lung histopathology, reduced inflammatory cytokines, downregulated PTGS2 and proteins in the CLR pathway, enhanced mitochondrial function, and decreased pyroptosis-related protein levels; consistent effects were observed in vitro. These findings indicate that berberine targets the CLR pathway, inhibits PTGS2, and restores mitochondrial and cellular homeostasis, thereby reducing inflammation and tissue damage in severe pneumonia.