Mechanistic insights into iron oxide nanoparticles-induced iron deregulation and mitochondrial dysfunction in yellow...

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.