Novel insights into DBP-induced zebrafish liver inflammatory damage: Ferroptosis activating the HMGB1-TLR4-NF-κB...

Typical plasticizer dibutyl phthalate (DBP) has been demonstrated to induce hepatotoxicity in zebrafish, but the underlying molecular mechanisms remain incompletely elucidated. Numerous studies have shown that ferroptosis is involved in the pathophysiological progression of hepatic disease. However, it remains unclear whether ferroptosis is involved in the DBP-induced hepatotoxicity in zebrafish. Initially, histopathological analyses have preliminarily confirmed that DBP can activate inflammatory responses in the zebrafish liver. Further investigation revealed that DBP induces ferroptosis in the zebrafish liver, characterized by iron overload, lipid peroxidation, and aberrant activation of ferroptosis pathways. Furthermore, DBP exposure induced ferroptosis, disrupting cell membranes and subsequent release of HMGB1, which are sensed by immunocytes TLR4/NF-κB signaling pathways, thereby activating the innate immune response in a context-dependent manner. Moreover, the ferroptosis inhibitor Fer-1 effectively rescues the activation of HMGB1-TLR4/NF-κB-mediated immune processes. Overall, this work enriches the molecular mechanism of DBP-induced zebrafish liver inflammatory damage and provides a reliable biomarker for future environmental risk assessment of DBP.