Circular RNA Gsr-0002 promotes schistosomiasis-induced liver fibrosis by regulating the DNMT3A/PTEN pathway

Hepatic fibrosis is the most serious pathological manifestation in schistosomiasis. Circular RNAs (circRNAs) are noncoding loop transcripts important in various diseases; however, the expression profile and function of circRNAs in liver fibrosis induced by schistosome infection remain unknown. Here, second-generation high-throughput sequencing of circRNAs in primary hepatic stellate cells (HSCs) isolated from livers of mice with Schistosoma japonicum-induced schistosomiasis identified 489 significantly differentially expressed circRNAs. The top 10 differentially expressed and consistently upregulated or downregulated circRNAs were further verified in primary HSCs and fibrosis liver tissue using qRT-PCR. Among them, circGsr-0002 expression increased after schistosome infection, consistent with significant increases in both activated HSCs and fibrotic liver tissue. Knockdown of circGsr-0002 inhibited HSCs activation and proliferation, induced apoptosis and attenuated mouse liver fibrosis. RNA immunoprecipitation and dual luciferase reporter assays showed that miR-383-3p interacted with circGsr-0002. Transfection with miR-383-3p inhibitors promoted HSCs activation, while co-transfection with small interfering circGsr-0002 RNA reversed an inhibitory effect. Sequestering miR-383-3p to regulate the PTEN pathway and promote HSC activation and proliferation, contributing to liver fibrosis. These results provide further understanding of the expression profile of circRNAs in HSCs from schistosomiasis-induced liver fibrosis and identify the DNMT3A/PTEN axis as a new pathway leading to liver fibrosis.