Epiberberine and Palmatine Alleviate Staphylococcus aureus-Induced Acute Lung Injury by Modulating Host Inflammatory Responses Involving Src/Syk Signaling

Abstract Acute lung injury (ALI) caused by bacterial infection is largely driven by dysregulated host inflammatory responses, highlighting the need for host-directed therapeutic strategies. In this study, we investigated alkaloids derived from Coptis chinensis , focusing on epiberberine and palmatine, in both in vivo and in vitro models of Staphylococcus aureus -induced ALI. Unlike conventional endotoxin-based models, a live bacterial infection system was employed to better capture the complexity of host-pathogen interactions. Treatment with epiberberine and palmatine markedly attenuated lung injury in mice, as evidenced by reduced inflammatory cell infiltration and alleviated histopathological damage, accompanied by decreased production of pro-inflammatory mediators (TNF-α, IL-1β, and RANTES) and differential regulation of IL-10. Consistent anti-inflammatory effects were observed in peritoneal macrophages following bacterial stimulation. Integrated transcriptomic profiling and network analysis identified Src and Syk as putative upstream regulators associated with infection-induced inflammatory responses. Both compounds were observed to suppress Src/Syk phosphorylation and downstream MAPK signaling, while pharmacological inhibition of Src or Syk produced comparable effects without additive responses. Collectively, these findings suggest that epiberberine and palmatine alleviate bacterial pneumonia-associated lung injury by modulating host inflammatory responses, potentially involving Src/Syk-associated signaling pathways, supporting their potential as candidates for host-directed therapy.