Adverse outcome pathway analysis identifies DRP1-driven mitochondrial dysfunction as a central event in silver...

Silver nanoparticles (AgNPs) are increasingly employed across diverse applications, raising concerns regarding their potential biosafety risks. The liver plays a pivotal role as a target organ upon exposure to AgNPs. The adverse outcome pathway (AOP) framework provides a structured, mechanism-based approach for assessing and managing toxicological risks.

In this study, we applied the AOP framework to construct a mechanistic relationship map of AgNP-induced hepatotoxicity. Using in vitro (HepG2 cells) and in vivo (C57BL/6 mice) models, we identified mitochondrial dysfunction as a molecular initiating event (MIE), characterized by excessive dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and increased mitochondrial reactive oxygen species (mtROS), which serve as key events (KEs). The cascade ultimately leads to programmed cell death and structural/functional liver injury, which constitute the AO. Further mechanistic investigations revealed that DRP1 phosphorylation at the Ser616 site activated sequestration 1 (p62)/PTEN-induced kinase 1 (PINK1)-dependent mitophagy, which partially mitigated the severity of the AO by preserving mitochondrial integrity and reducing oxidative damage.

These findings not only demonstrate the critical role of DRP1 activation in linking mitochondrial dynamics to hepatocellular ferroptosis, but also highlight the value of the AOP framework as a tool for predicting NPs risk assessment and regulatory decision-making.