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.