Liensinine reduces acute lung injury brought on by lipopolysaccharide by inhibiting the activation of the NF-κB signaling pathway through modification of the Src/TRAF6/TAK1 axis.

ALI is characterized by macrophage-driven inflammation, causing severe lung damage. Currently, there are limited therapeutic options available for ALI. Liensinine (LIEN), with known anti-inflammatory properties, lacks extensive study in the ALI context. This study aimed to investigate the impact of LIEN on ALI and elucidate its molecular mechanisms. A total of thirty-six male BALB/c mice altogether were split into six groups: Control, LPS (10 mg/kg), Low (10 mg/kg LIEN + 10 mg/kg LPS), Middle (20 mg/kg LIEN + 10 mg/kg LPS), High (40 mg/kg LIEN + 10 mg/kg LPS), and DEX (2 mg/kg DEX + 10 mg/kg LPS). Lung tissue injury, pulmonary edema, and inflammatory factor levels were evaluated in lung tissues and LPS-stimulated bone marrow-derived macrophages (BMDM). TAK1 activation, TRAF6 ubiquitination, and their interactions were assessed to understand the involved molecular mechanisms. LIEN treatment ameliorated lung tissue injury and suppressed LPS-induced inflammatory factor levels in lung tissues and BMDM. Mechanistically, LIEN inhibited TAK1 activation by disrupting TRAF6-TAK1 interactions, limiting p65's nuclear translocation, and reducing the release of inflammatory factors. According to network pharmacology and molecular docking, LIEN most likely prevents inflammation by interfering directly with the Src. Overexpression of Src in BMDM abolished the regulation of TRAF6 by LIEN, supporting the involvement of the Src/TRAF6/TAK1 axis in its mechanism of action. Based on this study, LIEN treats ALI by modifying the Src/TRAF6/TAK1 axis and blocking the activation of the NF-κB pathway, regulating the release of inflammatory factors. These findings highlight the promise of LIEN as a prospective therapeutic option for the treatment of ALI.