非酒精性脂肪性肝病（NAFLD）是我国第一大慢性肝病，严重危害公共健康。课题组前期发现：纳米SiO2可诱发NAFLD；芯片结果表明：miR-451可调控脂质合成限速酶ACSL4，但其调控机制不清。本项目拟深入研究纳米SiO2经miR-451/ACSL4铁死亡信号通路诱发NAFLD的分子机制。体内采用肥胖模型鼠和转基因斑马鱼研究纳米SiO2对肝脏功能的影响；检测肝脏脂含量、脂质过氧化和脂代谢相关基因表达改变，明确纳米SiO2对脂代谢及NAFLD的影响；测定肝脏铁离子和脂质活性氧水平，原位杂交结合MO基因沉默验证纳米SiO2对miR-451/ACSL4铁死亡通路的作用。体外构建肝细胞miR-451过表达和干扰体系，采用siRNA沉默ACSL4及铁死亡抑制剂，反向验证miR-451/ACSL4铁死亡信号通路在纳米SiO2诱发NAFLD的调控机制，项目可为纳米SiO2毒理学安全性评价提供科学依据。

The non-alcoholic fatty liver disease (NAFLD) is the NO.1 chronic liver disease in China which is threatening the public health. Our previous study found that silica nanoparticles (Nano-SiO2) could induce NAFLD; gene chip analysis revealed that miR-451 could regulate the key limiting enzyme ACSL4 of lipid synthesis, but the involved mechanism was still unclearly. This study is aimed to investigate the related mechanisms of Nano-SiO2 on NAFLD via miR-451/ACSL4 ferroptosis signaling pathway. The NAFLD is detected in ob/ob mice and transgenic zebrafish model after exposed to Nano-SiO2. The liver function is analyzed. The hepatic lipid contents, lipid peroxidation and metabolic genes are further measured to clarify the impact on hepatic lipid metabolism and NAFLD. Detecting the iron level and lipid ROS in liver, and adopting the in situ hybridization combined with MO silence to confirm the effects of Nano-SiO2 on miR-451/ACSL4 ferroptosis signaling pathway. Using miR-451 overexpression and knock-down system in hepatic cell line, combined with the siRNA knockdown of ACSL4 and ferroptosis inhibitor to analyze the changes in miR-451/ACSL4 ferroptosis signaling pathway to further verify the regulatory mechanisms of Nano-SiO2-induced NAFLD. This study will provide the scientific evidences for safety evaluation of Nano-SiO2.