Endothelial neuraminidase 1 inhibition attenuates LPS-induced acute lung injury through the CXCR4 pathway

Neuraminidase 1 (NEU1), a key sialidase in human pulmonary microvascular endothelial cells, plays a central role in idiopathic pulmonary fibrosis. However, its contribution to endothelial dysfunction in acute lung injury (ALI) remains unclear. Notably, although natural NEU1 inhibitors have been initially identified, their specific molecular mechanisms and potential therapeutic effects in ALI remain to be elucidated- a critical research gap hindering the translation of NEU1-targeted therapies into clinical practice for ALI. We established a mouse lung infection model and a cultured endothelial cell model stimulated by LPS. NEU1 knockdown, overexpression, and pharmacological inhibition were employed to assess its impact on endothelial inflammation and dysfunction. The interaction between NEU1 and its target proteins, as well as the downstream signaling pathways, were analyzed using surface plasmon resonance (SPR), co-immunoprecipitation (Co-IP), Western blotting, and signaling pathway analysis. Based on previous research, baicalin was screened as potential inhibitors of NEU1, and their effects and potential mechanisms were analyzed through in vitro and in vivo studies. This study demonstrates that NEU1 expression is elevated in LPS-induced endothelial cells and lung tissue in ALI mice, suggesting that NEU1 may serve as a key pathogenic factor in ALI. NEU1 knockdown or pharmacological inhibition alleviates endothelial inflammation and dysfunction, while its overexpression promotes inflammatory gene transcription in human aortic endothelial cells. Mechanistically, NEU1 directly interacts with CXCR4 to enhance its protein stability, which in turn activates the JNK signaling pathway and contributes to endothelial dysfunction. Endothelial-specific NEU1 knockdown reduces CXCR4 expression and alleviates LPS-induced ALI. Baicalin, a flavonoid from Scutellaria baicalensis Georgi, binds to NEU1, promoting its lysosome-dependent degradation and inhibiting the NEU1/CXCR4 axis. In vivo experiments further confirmed that baicalin significantly attenuates lung injury and improves pulmonary function in ALI. Additionally, Huang-Lian-Jie-Du decoction (HLJDD), a traditional Chinese medicine containing baicalin, demonstrates therapeutic efficacy against ALI by targeting NEU1/CXCR4 and reducing inflammatory responses, providing new evidence supporting the clinical application of traditional Chinese medicine for ALI treatment. This study establishes NEU1 as a critical driver of ALI and identifies baicalin and HLJDD as promising therapeutic interventions, providing a new theoretical basis and potential therapeutic targets for the clinical treatment of ALI.