MicroRNA miR-199a-3p alleviates liver fibrosis by targeting CDK17 in activated hepatic stellate cells.

Liver fibrosis, a common feature of most chronic liver diseases, poses significant health risks and results from various etiologies. While microRNAs (miRNAs) have demonstrated promising anti-fibrotic potential through the direct regulation of target genes, their therapeutic mechanisms remain incompletely understood. In this study, we identified miR-199a, initially discovered in anti-liver fibrotic exosomes, as a key modulator that alleviates thioacetamide-induced liver fibrosis in a mouse model. Consistent with its in vivo effects, treatment with an miR-199a mimic effectively inhibited the activation and function of human hepatic stellate cells (HSCs)-central drivers of liver fibrosis-as well as HSC proliferation and viability in vitro. Notably, miR-199a-3p exerted these anti-fibrotic effects by directly downregulating its biologically relevant target, cyclin-dependent kinase 17 (CDK17). Depletion of CDK17 alone in activated HSCs was sufficient to suppress their activation, function, proliferation, and viability, mirroring the effects of miR-199a mimic treatment. Conversely, overexpression of CDK17 reversed all cellular effects induced by miR-199a mimic treatment. Our findings highlight the miR-199a-3p-CDK17 regulatory axis and suggest that targeting CDK17 in activated HSCs could be a promising therapeutic strategy for liver fibrosis.