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MicroRNA miR-199a-3p alleviates liver fibrosis by targeting CDK17 in activated hepatic stellate cells
Min-Seok Choi1, Jae-Sang Hong1, Do-Hoon Lee1
1College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
Abstract:
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.
Insights
MicroRNAs (miRNAs) show potential against liver fibrosis. This study found miR-199a alleviates liver fibrosis by targeting CDK17 in hepatic stellate cells, offering a new therapeutic strategy.
Area of Science:
- Hepatology and molecular biology
- Cellular and molecular mechanisms of liver disease
Background:
- Liver fibrosis is a critical outcome of chronic liver diseases, driven by hepatic stellate cells (HSCs).
- MicroRNAs (miRNAs) are implicated in fibrosis, but their precise anti-fibrotic roles and targets require elucidation.
Purpose of the Study:
- To investigate the anti-fibrotic role of miR-199a in liver fibrosis.
- To identify the molecular targets and mechanisms underlying miR-199a's therapeutic effects.
Main Methods:
- Utilized a thioacetamide-induced mouse model of liver fibrosis.
- Administered miR-199a mimics to mice and human hepatic stellate cells (HSCs) in vitro.
- Investigated the direct interaction between miR-199a-3p and cyclin-dependent kinase 17 (CDK17).
- Assessed the effects of CDK17 manipulation (depletion and overexpression) on HSCs.
Main Results:
- miR-199a treatment significantly alleviated liver fibrosis in vivo.
- miR-199a inhibited human HSC activation, function, proliferation, and viability in vitro.
- miR-199a directly downregulated CDK17, a key regulator of HSCs.
- CDK17 depletion mimicked miR-199a's anti-fibrotic effects, while CDK17 overexpression reversed them.
Conclusions:
- The miR-199a-3p/CDK17 axis is a critical regulator of liver fibrosis.
- Targeting CDK17 in activated HSCs presents a potential therapeutic strategy for liver fibrosis.
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