MiR-383-5p promotes schistosomiasis-induced liver fibrosis by targeting peroxiredoxin-3

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BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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