Alleviating the Toxic Effects of Nitrite: Histidine Mitigates Hepatopancreas Damage by Suppressing Ferroptosis and Enhancing Mitochondrial Quality Control

Nitrite accumulation in aquaculture systems exerts diverse toxic effects, jeopardizing aquatic animal health and sustainable production. Although dietary amino acid supplementation has shown potential in mitigating stress in fish, the protective role of histidine remains unclear. This study investigated the mechanism by which dietary histidine alleviates nitrite-induced hepatotoxicity in grass carp. Our findings reveal that histidine not only ameliorated nitrite-induced alterations in blood parameters but also enhanced the antioxidant capacity. Crucially, histidine attenuated hepatopancreatic and mitochondrial damage by suppressing ferroptosis and coordinating mitochondrial quality control. Mechanistically, histidine attenuated ferroptosis probably by regulating the Nrf2 pathway and iron metabolism. It also maintained mitochondrial homeostasis by promoting fusion, inhibiting fission, and inducing mitophagy via PINK1/Parkin and BNIP3 signaling. These findings highlight histidine's protective effects against nitrite-induced hepatopancreas injury and suggest 10.82 g/kg as the optimal dietary level for enhancing nitrite resistance in grass carp, providing valuable insights for developing antistress aquafeeds.