Potential involvement of the PPARγ–SCD1–ferroptosis axis in AgNPs-associated hepatotoxicity

● AgNPs disrupted hepatic lipid metabolism and induced ferroptosis-related toxicity. ● AgNPs induced SCD1 upregulation associated with lipid dysregulation and ferroptosis. ● SCD1 may link lipid metabolism with PPARγ pathway and ferroptosis-related injury. ● AgNPs exposure was associated with insulin resistance– and T2DM-like alterations. Silver nanoparticles (AgNPs) are widely used nanomaterials, yet their potential metabolic and hepatic risks remain insufficiently understood. In this study, we investigated the toxicological effects of AgNPs in zebrafish and explored the potential involvement of a peroxisome proliferator-activated receptor γ (PPARγ)–stearoyl-CoA desaturase 1 (SCD1)–ferroptosis–related pathway associated with lipid metabolic disturbance and type 2 diabetes mellitus (T2DM)-like metabolic alterations. AgNPs exposure induced coordinated upregulation of PPARγ and SCD1 and downregulation of glutathione peroxidase 4 (GPX4), which were accompanied by hepatic lipid accumulation, oxidative stress, and ferroptosis-related responses in larvae, as indicated by elevated reactive oxygen species (ROS) and Fe 2+ levels, glutathione (GSH) depletion, and enhanced lipid peroxidation. These alterations persisted into adulthood and were accompanied by increased body and liver weight, dyslipidemia, hyperglycemia, and impaired insulin signaling, resembling T2DM-like phenotypes. Pharmacological inhibition further supported the involvement of this pathway: the ferroptosis inhibitor deferoxamine (DFO), the PPARγ antagonist 2-chloro-5-nitro-N-(pyridin-4-yl)benzamide (T0070907), and the SCD1 inhibitor 4-(2-chlorophenoxy)-N-[3-[(methylamino)carbonyl]phenyl]-1-piperidinecarboxamide (A939572) significantly alleviated AgNPs-associated hepatic injury. Mechanistic analyses suggest that SCD1, acting downstream of PPARγ, may function as a key mediator linking lipid metabolic dysregulation to ferroptosis. Collectively, these findings provide new insight into the metabolic toxicity associated with AgNPs exposure and contribute to improved ecological and biomedical safety assessment of engineered nanomaterials. Download: Download high-res image (382KB) Download: Download full-size image