Mechanistic insights into iron oxide nanoparticles-induced iron deregulation and mitochondrial dysfunction in yellow catfish Pelteobagrus fulvidraco: Comparison with ferrous sulphate.

Despite the widespread use of iron oxide nanoparticles (Fe2O3NPs) in various applications, their differential effects on iron metabolism and iron form-dependent toxicity relative to ferrous sulphate (FeSO4) remain unclear. In this study, we demonstrate that, Fe2O3NPs, in contrast to FeSO4, cause liver structural damage, promote hepatic iron accumulation, impair iron-sulfur cluster (ISC) biogenesis and induce mitochondrial dysfunction in yellow catfish Pelteobagrus fulvidraco. Mechanistically, Fe2O3NPs-induced oxidative stress suppresses NRF2 expression, thereby reducing transcription of frataxin (FXN), a crucial ISC biogenesis factor. This leads to impaired ISC biogenesis and downstream disruption of iron homeostasis. Notably, ISC-dependent F-box and leucine rich repeat protein 5 (FBXL5), which mediates ubiquitination and degradation of iron regulatory protein 2 (IRP2), exhibits reduced interaction with IRP2 following Fe2O3NPs exposure. As a result, stabilized IRP2 activates the IRP/IRE system and eventually increases the labile iron pool (LIP), which further contributes to mitochondrial dysfunction. Our findings demonstrate that FeSO4 and Fe2O3NPs elicit distinct hepatic antioxidant metabolic responses in yellow catfish, offering critical insights into the molecular mechanisms underlying nanoparticle-induced hepatotoxicity compared with inorganic salts.