Extracellular vesicles derived from HSCs transmitted circPVT1 to ameliorate oxidative damage to hepatocytes by...

Our previous studies demonstrated that extracellular vesicles (EVs) derived from quiescent hepatic stellate cells (HSC-EVs) exert protective effects against oxidative injury to hepatocytes. In this study, we aimed to clarify the hepatoprotective mechanisms of action of HSC-EVs. By RNA sequencing, circPVT1 was identified as a highly abundant circular RNA in HSC-EVs. Functionally, we observed that circPVT1 knockdown abolished the beneficial effects of HSC-EVs in improving liver function and increasing the proliferation and reducing the apoptosis of hepatocytes in a H₂O₂-treated hepatocyte model and in a CCL₄-induced liver injury rat model via delivering circPVT1. Bioinformatics analysis and dual luciferase assays revealed that circPVT1 acts as a molecular sponge for miR-125b-5p. Through a series of loss-and-gain experiments, we confirmed that circPVT1 increased the proliferation and reduced the apoptosis of hepatocytes through the inhibition of miR-125b-5p expression. Furthermore,rescue experiments revealed that overexpression of BCL2L2, a target gene of miR-125b-5p, restore the declined hepatoprotective effects of HSC-EVs with miR-125b-5p overpression. These findings demonstrate that HSC-EVs are potential therapeutic vesicles that can protect against oxidative injury to hepatocytes through the activation of the circPVT1/miR-125b-5p/BCL2L2 signalling pathway.