Table 2.

The role of EVs derived from fluke worms in CCA progression.

Fluke-Worm-Derived EVs	Role in CCA Progression
O. viverrine-derived EVs [89,93]	Modified wound-healing process Dysregulation of several protein expression ↑ IL-6 cytokine release/↑ cell proliferation Cholangiocarcinogenesis ↑ parasite-secreted granulin Intercellular crosstalk between CCA-secreted EVs and naïve cholangiocytes Modulation of MAPK phosphorylation in naïve cholangiocytes
C. sinensis-derived EVs [90,91,92]	EV-contained Csi-let-7a-5p are internalized by M1-type macrophages. Inhibition of Clec7a and Socs1 Deregulation of NF-κΒ pathway ↑ proinflammatory state Overexpression of TLR4 ↑ biliary tract fibrosis via NF-κB-TGF-b-TLR4 signaling pathway Upregulation of ERK, AKT, p65, and p38 in BECs TNF-a, IL6 oversecretion via TLR9 expression in BECs

(O. viverrini) Opistorchis viverrini, (C. sinensis) Clonorchis sinensis, (BECs) biliary epithelial cells, (TLR9) toll-like receptor 9, (TLR3) toll–like receptor-3, ↑ upregulated.