Red blood cell damage defines the etiology of hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids

Hepatic sinusoidal obstruction syndrome (HSOS), a life-threatening liver disease characterized by sinusoidal endothelial cell (LSEC) damage, is frequently caused by pyrrolizidine alkaloid (PA) exposure present in numerous herb or food products. Unlike other hepatotoxins, the precise mechanism by which PAs selectively target LSECs remains poorly understood, posing significant challenges to the development of effective treatments. This study identified hemolysis as the initiating event in PA-HSOS pathogenesis through clinical and animal model analyses. PA exposure induced red blood cell (RBC) rupture, releasing free hemoglobin (Hb) that directly damaged LSECs. Mechanistic investigations revealed that PA-formed protein adducts with haptoglobin (Hp), impairing its protective effect against toxic Hb and triggering a cascade of LSEC activation, ferroptosis, and hemorrhagic liver necrosis. Rescue study revealed that Hp supplementation effectively mitigated PA-induced liver injury by scavenging free Hb. Clinical validation demonstrated elevated Hb-Hp adducts and cell-free Hb in PA-HSOS patients, confirming concordant intoxication mechanisms across species. The findings redefine PA-HSOS as a hematogenous liver disorder originating from RBC destabilization, rather than direct hepatocyte toxicity. This hematopathological perspective reveals Hp replacement therapy as a promising etiological treatment strategy, addressing the root cause rather than secondary liver damage.