Serpine1 as a potential therapeutic target in pyrrolidine alkaloids-induced hepatic sinusoidal obstruction syndrome

Background & Aims Hepatic sinusoidal obstruction syndrome (HSOS) induced by pyrrolizidine alkaloids (PAs) is a life-threatening liver injury for which standardized chronic models are lacking. This study aimed to establish a clinically relevant chronic PA-HSOS murine model and to identify potential therapeutic targets. Methods A 28-day model was developed using key alkaloids from Gynura segetum (seneciphylline, senecionine, and N-oxide derivatives), mirroring human exposure. Disease characteristics were evaluated via hematological profiling, CT imaging, histopathology, and transcriptomics. A hepatocyte–liver sinusoidal endothelial cell (LSEC) co-culture system was used to validate molecular mechanisms. TM5441, a Serpine1 inhibitor, was evaluated for therapeutic efficacy. Results The model faithfully recapitulated human HSOS, characterized by elevated liver enzymes (ALT, 1.6-fold, p < 0.001; AST, 5.7-fold, p < 0.0001, n=6), coagulation dysfunction (prothrombin time, 1.5-fold, p < 0.001; activated partial thromboplastin time, 1.1-fold, p < 0.05; D-dimer, 8.4-fold, p < 0.0001, n=6), increased liver weight (1.2-fold, p < 0.0001, n=6), reduced VE-cadherin expression (0.28-fold, p < 0.001, n=6), and sinusoidal fibrosis. RNA sequencing identified Serpine1 as the most significantly upregulated gene (|log 2 fold-change| ≥2, p