慢性乙型肝炎（CHB）危害严重，大量研究证实部分持续ALT正常（PNALT）患者存在显著肝损伤，尽早发现这类患者的肝脏损伤并给予抗病毒治疗是关键。本课题前期在PNALT的CHB 患者中通过高通量测序筛选出外泌体miR-25-3p/miR-425-5p与肝脏炎症程度密切相关，并确认了miR-25-3p的下游靶基因为肝脏炎症和免疫相关基因TLR3、TRAF6和EGR2。本研究拟首先扩大临床样本量，探讨这两个miRNAs对肝脏炎症早期诊断的可行性；接着通过荧光标记的手段研究外泌体在肝细胞中的转运，共培养外泌体与受体肝细胞，分析外泌体miRNAs对肝细胞炎症损伤和免疫信号调节的影响；最后构建慢性肝损伤小鼠模型，观察外泌体miRNAs影响肝脏炎症的机制及抗乙肝病毒的免疫治疗作用。阐明外泌体miR-25-3p/miR-425-5p对PNALT的早期肝损伤的诊断价值，为该类患者抗病毒治疗提供新思路。

Chronic hepatitis B (CHB) is fatal. A large number of studies have shown that there are significant liver injuries in some patients with persistent normal ALT (PNALT). Early detection of liver injury and antiviral therapy is very important. Our previous study showed that exosome-derived miR-25-3p / miR-425-5p in PNALT CHB patients by high-throughput sequencing was closely related to the degree of liver inflammation, and confirmed that the downstream target gene of miR-25-3p was liver inflammation and immune-related genes such as TLR3, TRAF6 and EGR2. In this study, we first expand the clinical sample size to explore the feasibility of these two miRNAs in the diagnosis of early liver injury; then analyzed the effects of exosome miRNAs on hepatocyte inflammatory injury and immune signal regulation followed by fluorescence labeling of exosomes in liver cell transport, co-culture of exosomes and recipient hepatocytes. Finally, constructed the chronic liver injury model mice to observe the mechanism of exogenous miRNAs affecting hepatic inflammatory injury and the anti-hepatitis B virus immunotherapy in vivo. Thereby, the study elucidate the significance of exosomal miR-25-3p/miR-425-5p as novel candidate for early liver injury and treatment of PNALT.