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Abstract：
Schistosomiasis is a parasitic disease characterized by liver fibrosis, a process driven by the activation of hepatic stellate cells (HSCs) and subsequent collagen production. Previous studies from our laboratory have demonstrated the ability of Schistosoma japonicum protein P40 (SjP40) to inhibit HSCs activation and exert an antifibrotic effect. In this study, we aimed to elucidate the molecular mechanism underlying the inhibitory effect of recombinant SjP40 (rSjP40) on HSCs activation. Using a cell model in which rSjP40 inhibited LX-2 cell activation, we performed RNA-seq analyses and identified ATF3 as the most significantly altered gene. Further investigation revealed that rSjP40 inhibited HSCs activation partly by suppressing ATF3 activation. Knockdown of ATF3 in mouse liver significantly alleviated S. japonicum-induced liver fibrosis. Moreover, our results indicate that ATF3 is a direct target of microRNA-494-3p, a microRNA associated with anti-liver fibrosis effects. rSjP40 was found to downregulate ATF3 expression by upregulating microRNA-494-3p in LX-2 cells. This downregulation led to the inhibition of the expression of liver fibrosis proteins α-SMA and COL1A1, ultimately alleviating liver fibrosis caused by S. japonicum.
摘要：
血吸虫病是一种以肝纤维化为特征的寄生虫病,由肝星状细胞（HSC）的激活和随后的胶原蛋白产生驱动的过程。我们实验室的先前研究已经证明了日本血吸虫蛋白P40（SjP40）抑制HSC活化并发挥抗纤维化作用的能力。在这项研究中,我们旨在阐明重组SjP40(rSjP40)抑制HSCs活化的分子机制。使用rSjP40抑制LX-2细胞活化的细胞模型，我们进行了RNA-seq分析,确定ATF3为最显著改变的基因.进一步的研究表明，rSjP40部分通过抑制ATF3活化来抑制HSC活化。在小鼠肝脏中敲除ATF3可显着减轻日本血吸虫诱导的肝纤维化。此外，我们的结果表明ATF3是microRNA-494-3p的直接靶标，与抗肝纤维化作用相关的microRNA。发现rSjP40通过上调LX-2细胞中的microRNA-494-3p下调ATF3表达。这种下调导致肝纤维化蛋白α-SMA和COL1A1的表达受到抑制，最终缓解了日本血吸虫引起的肝纤维化。
