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Background: Hepatic sinusoidal obstruction syndrome (HSOS) is a fatal vascular liver disease characterized by liver sinusoidal endothelial cell (LSEC) injury. Exposure to pyrrolizidine alkaloids (PAs), the most common plant toxins found in herbal medicines and contaminated food products, is a leading cause of HSOS. However, why PAs specifically damage LSEC rather than initially targeting hepatocytes, as seen with other hepatotoxins such as acetaminophen, remains a long-standing puzzle. This study addresses this question from a novel hematopathologic perspective.
Methods: Protein adduction analysis was performed on both experimental animal models and clinical samples from PA-intoxicated patients. Blood protein targets of PAs were identified, and their pathological roles in LSEC damage and HSOS progression were investigated using in vitro and in vivo models.
Central Findings: PAs characteristically induced abundant protein adducts in red blood cells (RBCs) and plasma. Specifically, PA-derived reactive metabolites adducted RBC glucose-6-phosphate dehydrogenase (G6PD) and plasma haptoglobin, leading to accumulation of oxidative hemolytic products. This triggered a pathogenic cascade of LSEC activation, LSEC damage, hepatocyte ferroptosis, and HSOS development. Based on these distinct blood protein targets, an etiological therapeutic strategy was developed with translational potential.
Conclusions: PA-induced HSOS is a "hepatopathy with hematopathy origin." Targeting hematopathy, specifically PA-induced RBC damage and hemolytic product accumulation, represents a promising etiological therapeutic approach for this fatal vascular liver disease.