Csi-miR-71a delivered by Clonorchis sinensis extracellular vesicles suppresses liver fibrosis by targeting Scube3 to inhibit the TGF-β/Smad and PI3K/AKT signaling pathways.

Lentiviral delivery of Csi-miR-71a in a CCl4-induced mouse model alleviates liver fibrosis by directly targeting Scube3 and suppressing TGF-β/Smad and PI3K/AKT signaling.

• Why it matters: Liver fibrosis in the host is linked to C. sinensis–driven activation of hepatic stellate cells, but how parasite EV miRNAs regulate fibrosis remains unclear.
• What they did: EVs from C. sinensis excretory-secretory products were isolated and shown to be taken up by HSC-T6 cells; small RNA sequencing found Csi-miR-71a enriched in EVs and infected HSCs. Functional tests used miRNA mimics/inhibitors and lentiviral delivery in HSC-T6 cells, primary HSCs, and mouse liver tissue, with dual-luciferase and co-immunoprecipitation identifying Scube3 as a direct target.
• The result: Csi-miR-71a overexpression reduced fibrotic markers and collagen deposition, while inhibition increased them; Scube3 silencing lowered Smad2/3 and PI3K/AKT phosphorylation, and SCUBE3 restoration rescued fibrosis-associated proteins and reactivated both pathways.

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