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Shanshan Hou,1 Chao Li,2 Yihua Wang,3 Jiayin Sun,2 Yutong Guo,4 Xiaofan Ning,1 Kai Ma,1 Xinyue Li,1 Hua Shao,2 Guanqun Cui,5 Minghua Jin,1 Zhongjun Du2 1School of Public Health Jilin University, Changchun, Jilin Province, 130021, the People’s Republic of China; 2Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250062, the People’s Republic of China; 3Chemical Institute of Chemical Industry, Xinjiang University of Science and Technology, Korla, Bayinguoleng Mongolian Autonomous Prefecture, Xinjiang Uygur Autonomous Region, 841000, the People’s Republic of China; 4Navel Medical University, Shanghai, 200433, the People’s Republic of China; 5Department of Respiratory Medicine, Children’s Hospital Affiliated to Shandong University, Ji’nan, Shandong Province, 250022, the People’s Republic of ChinaCorrespondence: Minghua Jin, School of Public Health, Jilin University, Changchun, Jilin Province, 130021, the People’s Republic of China, Email jinmh@jlu.edu.cn Zhongjun Du, Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250062, the People’s Republic of China, Email duzj1981@163.comIntroduction: Silica nanoparticles (SiNPs) have been widely used in food, cosmetics, medicine and other fields; however, there have been growing concerns regarding their potential adverse effects on health. A large number of studies have confirmed that SiNPs with small particle diameters can pass through the blood brain barrier, causing irreversible damage to the nervous system. This study aims to further explore the molecular mechanism of neurotoxicity of SiNPs and provide a toxicological basis for the medical application of SiNPs.Methods: We conducted an in vitro study using neuroimmune cells (mouse microglial cells, BV2) of the central nervous system to study inflammation and ferroptosis after exposure to SiNPs. We detected cell viability, morphology and ultrastructure, antioxidant function, inflammation, and ferroptosis-related proteins to explore the role of pyroptosis and ferroptosis in the damage of BV2 cells induced by SiNPs. We further explored the relationship between the inflammatory response and ferroptosis induced by SiNPs by silencing the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) gene and inhibiting ferroptosis.Results: The results showed that SiNPs could invade the cytoplasm, change the ultrastructure, activate NLRP3 inflammasomes, release a large number of inflammatory factors, and trigger inflammatory reaction. We also found that SiNPs could disrupt cellular antioxidant function, increase intracellular ferrous ion level and induce ferroptosis. In addition, both inflammation and ferroptosis are alleviated in NLRP3 gene-silenced cells.Conclusion: SiNPs could induce BV2 cytotoxicity through inflammatory response and ferroptosis, which may be mediated by the activation of the NLRP3 inflammasomes.Keywords: SiNPs, microglia, inflammation, ferroptosis, molecular mechanism