The neonicotinoid Imidacloprid provokes Ferritinophagy/Ferroptosis Axis disruption in rats' liver: The attenuation impact of Berberine chloride-loaded nano-liposomes.

Imidacloprid (IMI) is a widely applied insecticide, with evidence linking chronic exposure to toxic effects, particularly hepatotoxicity. Recently, ferroptosis has been nominated as a new contributor to hepatotoxicity-related cell death. This study was designed to investigate whether ferroptosis and ferritinophagy are involved in IMI-induced liver injury and to explore the potential protective effect of berberine chloride-PEGylated lipid nanoparticles (BC-PL). Berberine is a well-known alkaloid with documented hepatoprotective activity. Accordingly, adult male rats in six groups were administered two doses of IMI (22.5 and 45 mg/kg), with or without 10 mg/kg of BC-PL daily for 30 days. Liver enzymes, hepatic ferrous (Fe2+) levels, markers of oxidative stress, inflammation, ferritinophagy, and ferroptosis, as well as morphological changes, were analyzed. IMI significantly elevated liver enzymes, hepatic Fe2+, oxidative stress, and inflammatory markers. It also adversely affected the expression of ferritinophagy and ferroptosis markers, upregulating nuclear receptor coactivator 4 (NCOA4), ferritin heavy chain (FTH-1), transferrin receptor 1 (TFR1), and Keap1, while downregulating glutathione peroxidase (GPx), solute carrier family 7 member 11 (SLC7A11), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). IMI-induced hepatotoxicity was further confirmed by light and electron microscopy, and hepatic injury was directly associated with IMI dosage. Administration of BC-PL mitigated IMI-induced liver damage, as evidenced by improvements in biochemical and histopathological changes. This study thus sheds light on the possible role of the ferritinophagy/ferroptosis axis in IMI-induced hepatotoxicity, and that the inhibition of ferritinophagy contributes to the efficacy of BC-PL as a nano-formulated hepatoprotective system.