Inflammation and fibrosis are major consequences of autoimmune hepatitis, however, the therapeutic mechanism remains to be investigated. USP4 is a deubiquitinating enzyme and plays an important role in tissue fibrosis and immune disease. Vialinin A is an extract from mushroom and is a specific USP4 inhibitor. However, there is lack of evidences that Vialinin A plays a role in autoimmune hepatitis. By employing S100‐induced autoimmune hepatitis in mice and AML12 cell line, therapeutic mechanism of Vialinin A was examined. Inflammation was documented by liver histological staining and inflammatory cytokines. Fibrosis was demonstrated by Masson, Sirius red staining and fibrotic cytokines with western blot and real‐time RT‐PCR. In experimental animal, there were increases in inflammation and fibrosis as well as USP4, and which were reduced after treatment of Vialinin A. Vialinin A also reduced Rheb and phosphorylated mTOR. Moreover, in LPS‐treated AML12 cells, LPS‐induced USP4, inflammatory and fibrotic cytokines, phosphorylated mTOR and Rheb. Specific inhibitory siRNA of USP4 reduced USP4 level and the parameters mentioned above. In conclusion, USP4 was significantly elevated in autoimmune hepatitis mice and Vialinin A reduced USP4 level and attenuate inflammation and fibrosis in the liver. The mechanism may be related to regulation of Rheb/mTOR signalling.

中文翻译：

---

普遍特异性蛋白酶 4 抑制剂-Vialinin A 通过 Rheb/mTOR 信号通路减轻 S100 诱导的肝炎小鼠的炎症和纤维化

炎症和纤维化是自身免疫性肝炎的主要后果，然而，治疗机制仍有待研究。USP4是一种去泛素化酶，在组织纤维化和免疫疾病中起重要作用。Vialinin A 是一种蘑菇提取物，是一种特异性 USP4 抑制剂。然而，缺乏证据表明Vialinin A在自身免疫性肝炎中起作用。通过在小鼠和 AML12 细胞系中使用 S100 诱导的自身免疫性肝炎，研究了 Vialinin A 的治疗机制。通过肝脏组织学染色和炎性细胞因子记录炎症。Masson、天狼星红染色和纤维化细胞因子通过蛋白质印迹和实时 RT-PCR 证实了纤维化。在实验动物中，炎症和纤维化以及 USP4、并且在 Vialinin A 处理后减少。 Vialinin A 还减少了 Rheb 和磷酸化的 mTOR。此外，在 LPS 处理的 AML12 细胞中，LPS 诱导的 USP4、炎症和纤维化细胞因子、磷酸化的 mTOR 和 Rheb。USP4的特异性抑制siRNA降低了USP4水平和上述参数。总之，USP4 在自身免疫性肝炎小鼠中显着升高，而 Vialinin A 降低了 USP4 水平并减轻了肝脏的炎症和纤维化。该机制可能与 Rheb/mTOR 信号的调节有关。USP4 在自身免疫性肝炎小鼠中显着升高，而 Vialinin A 降低了 USP4 水平并减轻了肝脏中的炎症和纤维化。该机制可能与 Rheb/mTOR 信号的调节有关。USP4 在自身免疫性肝炎小鼠中显着升高，而 Vialinin A 降低了 USP4 水平并减轻了肝脏中的炎症和纤维化。该机制可能与 Rheb/mTOR 信号的调节有关。