Li Yi-Xin, Zhang Xin-Yue, Lu Ju-Lu, Yang Ying-Ying, Mei Cong-Jin, Dong Pan-Pan, Yu Chuan-Xin, Zhang Jian-Feng, Xiong Chun-Rong, Song Li-Jun, Yang Kun
National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Provincial Medical Key Laboratory, Jiangsu Institute of Parasitic Diseases, Wuxi, 214064, China.
Parasit Vectors. 2025 Jun 3;18(1):205. doi: 10.1186/s13071-025-06824-w.
Schistosomiasis-induced liver fibrosis, a major complication of infection, arises primarily from the host immune response to schistosome eggs. The mechanisms underlying the development of liver fibrosis remain unclear, but microRNAs (miRNAs) are thought to play a crucial role in this process. Our previous study revealed significantly reduced miR-383-5p expression in patients with advanced schistosomiasis, particularly in those with newly developed disease, suggesting a possible association between miR-383-5p and fibrotic progression. This study explores the role and mechanism of miR-383-5p in schistosomiasis-induced liver fibrosis.
The target gene of miR-383-5p was predicted through bioinformatics analysis. The expression levels of miR-383-5p and its target gene in the livers of Schistosoma japonicum (S. japonicum)-infected mice were investigated. Dual-luciferase reporter assays and miR-383-5p mimics and inhibitors were transfected of into LX-2 cells to determine the regulation of miR-383-5p on its target gene. AAV-8-overexpressing miR-383-5p vector injected into mice infected with S. japonicum, the target gene expression level, fibrosis-related factors, and pathological changes of liver were evaluated. The target gene knockout mice were infected with S. japonicum, and the degree of liver fibrosis was detected.
Target gene prediction identified peroxiredoxin 3 (PRDX3), a mitochondrial peroxidase that scavenges reactive oxygen species (ROS), as a target of miR-383-5p. During the progression of schistosome infection in mice, the expression level of miR-383-5p in the liver gradually decreased, reaching its lowest level 6 weeks after infection, at the peak of inflammation in egg granulomas, then gradually increasing, while the expression kinetics of PRDX3 were opposite to those of miR-383-5p. Using dual-luciferase reporter assays and transfection of miR-383-5p mimics and inhibitors into LX-2 cells, we confirmed that miR-383-5p directly targeted the 3' untranslated region (UTR) of PRDX3, leading to decreased mRNA levels of PRDX3. AAV8-mediated miR-383-5p overexpression and PRDX3 knockout in the mice infected with S. japonicum led to increased hepatic ROS and promoted the schistosomiasis-induced liver fibrosis.
Our findings suggest that downregulating miR-383-5p after schistosome infection may alleviate liver inflammation by de-repressing PRDX3, thereby increasing ROS scavenging and reducing oxidative stress. This study elucidates the role of the miR-383-5p/PRDX3 axis in schistosomiasis-induced liver fibrosis, suggesting that PRDX3 is a potential therapeutic target for this disease.
血吸虫病所致肝纤维化是感染的主要并发症，主要源于宿主对血吸虫卵的免疫反应。肝纤维化发展的潜在机制尚不清楚，但微小RNA（miRNA）被认为在此过程中起关键作用。我们之前的研究发现，晚期血吸虫病患者，尤其是新发病患者，miR-383-5p表达显著降低，提示miR-383-5p与纤维化进展可能存在关联。本研究探讨miR-383-5p在血吸虫病所致肝纤维化中的作用及机制。
通过生物信息学分析预测miR-383-5p的靶基因。研究日本血吸虫感染小鼠肝脏中miR-383-5p及其靶基因的表达水平。将双荧光素酶报告基因检测法以及miR-383-5p模拟物和抑制剂转染至LX-2细胞，以确定miR-383-5p对其靶基因的调控作用。将过表达miR-383-5p的腺相关病毒8型（AAV-8）载体注入日本血吸虫感染的小鼠体内，评估靶基因表达水平、纤维化相关因子及肝脏病理变化。用靶基因敲除小鼠感染日本血吸虫，检测肝纤维化程度。
靶基因预测确定过氧化物酶体增殖物激活受体3（PRDX3），一种清除活性氧（ROS）的线粒体过氧化物酶，为miR-383-5p的靶标。在小鼠血吸虫感染过程中，肝脏中miR-383-5p的表达水平逐渐降低，在感染后6周降至最低水平，此时正是虫卵肉芽肿炎症高峰期，随后逐渐升高，而PRDX3的表达动力学与miR-383-5p相反。通过双荧光素酶报告基因检测法以及将miR-383-5p模拟物和抑制剂转染至LX-2细胞，我们证实miR-383-5p直接靶向PRDX3的3'非翻译区（UTR），导致PRDX3的mRNA水平降低。AAV8介导的miR-383-5p过表达以及日本血吸虫感染小鼠中的PRDX3敲除导致肝脏ROS增加，并促进血吸虫病所致肝纤维化。
我们的研究结果表明，血吸虫感染后miR-383-5p下调可能通过解除对PRDX3的抑制来减轻肝脏炎症，从而增加ROS清除并降低氧化应激。本研究阐明了miR-383-5p/PRDX3轴在血吸虫病所致肝纤维化中的作用，提示PRDX3是该疾病的潜在治疗靶点。
