Dihydrotanshinone Alleviates Lipopolysaccharide‐Induced Acute Lung Injury by Targeting <scp>NEK7</scp> to Inhibit <scp>NLRP3</scp> Inflammasome Activation

Acute lung injury (ALI) carries high mortality with limited treatment options. Dihydrotanshinone (DHT), a bioactive component of Radix Salviae Miltiorrhizae, exhibits anti-inflammatory properties, though its molecular targets remain unclear. Given the critical role of NIMA-related kinase 7 (NEK7)-mediated NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation in inflammatory diseases, this study investigated DHT's anti-inflammatory effects through NEK7-NLRP3 regulation. In vitro, lipopolysaccharide (LPS) + ATP-stimulated macrophages were used to activate the NLRP3 inflammasome. In vivo, ALI was induced in BALB/c mice via intratracheal LPS instillation (4 mg/kg). NEK7 knockdown was achieved through intravenous and intranasal delivery of NEK7 siRNA. Protein expression of NEK7-NLRP3 components was analyzed in both models. Results indicated that LPS + ATP stimulation significantly upregulated NEK7-NLRP3 inflammasome components (NEK7, NLRP3, c-caspase-1, c-IL-1β) in macrophages and ALI tissues. DHT inhibited NEK7-NLRP3 complex formation, suppressing inflammasome assembly and activation. NEK7 knockdown eliminated IL-1β secretion in vitro and alleviated ALI in vivo. DHT treatment prevented pulmonary injury and reduced neutrophil infiltration. This study identifies DHT as a novel NEK7-NLRP3 inflammasome inhibitor, demonstrating its therapeutic potential for ALI treatment. These findings provide a new pharmacological approach targeting NEK7-mediated inflammasome activation in inflammatory lung diseases.