Quercetin Protects against Silicon dioxide Particles-induced spleen ZBP1-Mediated PANoptosis by regulating the Nrf2/Drp1/mtDNA axis

Silicon dioxide particles (SiO₂) are a widely used novel material, and SiO₂ that enter the body can accumulate in the spleen and cause spleen injury. Quercetin (Que) has a strong antioxidant activity and can also regulate and improve immune function, but whether Que can improve SiO2-induced spleen injury and its underlying mechanism remain to be explored. Herein, we established a C57BL/6 mice model with SiO₂ exposure (10 mg/kg) and treated with Que (25 mg/kg). We also cultured CTLL-2 cells for in vitro experiments. Studies in vivo and in vitro showed that SiO₂ exposure caused oxidative stress and mitochondrial dynamics disorder, which led to decrease of mitochondrial membrane potential (ΔΨm) and mitochondrial DNA (mtDNA) leakage. mtDNA was recognized by Z-DNA binding protein 1 (ZBP1) in the cytoplasm and increased the expression of ZBP1. This process further promoted the assembly of the ZBP1-mediated PANoptosome, which subsequently induced PANoptosis. Interestingly, supplementation with Que significantly reversed these changes. Specifically, Que mitigated spleen ZBP-1 mediated PANoptosis through preventing mtDNA leakage via regulating nuclear factor erythroid 2-related factor 2/Reactive Oxygen Species/dynamin-related protein 1 (Nrf2/ROS/Drp1) axis. This study enriches the understanding of the toxicological mechanisms of SiO₂ and provides evidence for the protective effects of Que against SiO₂-induced splenic toxicity.

Drp1; Keap1/Nrf2; PANoptosis; Quercetin; Silicon dioxide particles; mtDNA.