Nrf2 Activation Mitigates Silver Nanoparticle-Induced Ferroptosis in Hepatocytes

Silver nanoparticles (AgNPs), a promising class of metallic nanomaterials with strong antibacterial properties and biomedical potential, are increasingly being used in a variety of consumer products. The widespread application of AgNPs has raised concerns about their toxicological effects, particularly their accumulation in the liver and the associated oxidative stress. However, the precise molecular mechanisms driving these effects remain unclear. In this study, we provide evidence that AgNPs trigger ferroptosis in both mouse hepatocytes and HepG2 cells. Transcriptomic analysis identified ferroptosis is a primary cellular response to AgNP exposure, with Nrf2 serving a protective function. Specifically, AgNPs increased p62 expression, which in turn stabilized Nrf2 by suppressing its interaction with Keap1. Upon activation, Nrf2 enhances the transcription of key antioxidant enzymes, including NQO1 and HO-1, thereby alleviating ferroptosis. Additionally, we discovered that Nrf2 activation regulates iron storage by modulating FTH and FTL expression, thereby mitigating AgNP-induced ferroptosis in hepatocytes. These findings clarify the molecular basis of AgNP-induced ferroptosis in hepatocytes and underscore the crucial role of Nrf2 signaling in counteracting oxidative stress and ferroptosis.