Harmine Derivatives Alleviate LPS-Induced Acute Lung Injury via Targeting GSK3β

Acute lung injury (ALI) is a life-threatening inflammatory disorder with limited therapeutic options. This study evaluated the anti-inflammatory activity of ZLWH-38, a novel harmine derivative, in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and a murine ALI model. ZLWH-38 showed low cytotoxicity and effectively inhibited the production of nitric oxide and pro-inflammatory cytokines. In macrophages, it dose-dependently reduced the expression of TNF-α, IL-6, IL-1β and iNOS, and intracellular ROS levels. Mechanistic investigations indicated that ZLWH-38 interacted with glycogen synthase kinase-3β (GSK3β) and suppressed downstream NF-κB signaling. In female C57BL/6 mice subjected to LPS-induced lung injury, prophylactic administration of ZLWH-38 markedly attenuated histopathological damage, lowered the lung wet/dry weight ratio, and decreased neutrophil infiltration and cytokine levels in bronchoalveolar lavage fluid and lung tissue. These findings suggest that ZLWH-38 ameliorates ALI by blocking GSK3β and thereby repressing downstream NF-κB signaling to curtail inflammation, offering a novel rationale and mechanistic foundation for ALI therapeutics.