Molecular mechanism of tea polyphenols in alleviating tetrabromobisphenol A (TBBPA)-induced PANoptosis in carp (Cyprinus carpio) livers based on network toxicology and pharmacology

Tetrabromobisphenol A (TBBPA), characterized by extensive industrial utilization and low biodegradability, exhibits significant bioaccumulation potential in aquatic ecosystems, thereby posing substantial toxicological risks to aquatic organisms. Tea polyphenols (TP) are plant extracts with anti-inflammatory and antioxidant therapeutic potential. In this study, network toxicology and pharmacology approaches were employed to investigate the hepatotoxic mechanism of TBBPA and the hepatoprotective mechanism of TP in carp. Network analysis revealed that TBBPA-induced liver injury occurred primarily through oxidative stress, apoptosis, and inflammation. Conversely, TP was predicted to exert hepatoprotective effects mainly by regulating apoptosis and oxidative stress, with B-cell lymphoma-2 (Bcl-2) proteins playing a crucial role. Histopathological analysis showed that TBBPA induced structural damage to livers, which was attenuated by TP. Further experimental validation demonstrated that TBBPA induced oxidative stress in carp livers with the decreased activities of antioxidant enzymes (Superoxide Dismutase (SOD), Catalase (CAT), Glutathione (GSH), Total Antioxidant Capacity (T-AOC)) and excessive Reactive Oxygen Species (ROS). It also promoted the mRNA and protein expressions of inflammatory factors (Interleukin-6 (IL-6), Interleukin-1β (IL-1β), Tumor Necrosis Factor-alpha (TNF-α)), activated the NF-κB/MAPK pathway (elevated expressions of NF-κB-p65, Extracellular Regulated protein Kinases (ERK), p38 et al.), and triggered PANoptosis (apoptosis, necroptosis, pyroptosis). All these TBBPA-induced effects were alleviated by TP. In vitro validation using L8824 cells, quantified by flow cytometry, further confirmed that TP attenuated TBBPA-induced oxidative stress and apoptosis. This study further clarifies the mechanism of TBBPA hepatotoxicity in carp and provides a theoretical basis for adding TP to carp diet as a potential hepatoprotective agent.