Microtubule-Targeting Drugs Induce Mesenchymal-Epithelial Transition in Hepatic Stellate Cells.

BACKGROUND AND AIMS: Liver fibrosis is a progressive pathological condition characterized by excessive extracellular matrix accumulation, primarily driven by activated hepatic stellate cells (HSCs). While molecular-based strategies have been extensively explored for HSC deactivation, clinically effective therapies remain elusive. Previous studies suggest that epithelial-like features of quiescent HSCs are lost upon activation, implying that mesenchymal-epithelial transition (MET) may be a potential therapeutic mechanism for reversing HSC activation.

METHODS: To identify compounds capable of reprogramming HSCs, we screened a library of 1134 FDA-approved drugs using human HSCs (HHSteCs). Morphological changes were quantified by the axial ratio, and functional assays included proliferation, immunofluorescence, Western blotting, and qPCR. Mechanistic analyses focused on microtubule integrity, focal adhesion signalling, and YAP/TAZ activity. Antifibrotic effects in vivo were evaluated using a carbon tetrachloride (CCl4)-induced mouse fibrosis model treated with febantel, the prodrug of fenbendazole.

RESULTS: Five compounds, including taxanes and benzimidazoles, induced epithelial-like morphology and suppressed HSC activation. All shared the ability to disrupt microtubule dynamics. Fenbendazole exerted the strongest effect, reducing mesenchymal markers while restoring E-cadherin expression. Mechanistically, fenbendazole impaired focal adhesion signalling, attenuated YAP/TAZ activity, and promoted reassembly of adherens junctions, consistent with durable MET-like reprogramming. In vivo, febantel administration suppressed α-SMA and collagen1α1 expression and downregulated fibrogenic genes without altering serum markers of hepatocellular injury.

CONCLUSIONS: Our findings identify microtubule-dynamics inhibitors as potent inducers of MET-like reprogramming in HSCs. Fenbendazole, in particular, promotes HSC inactivation by linking microtubule disruption to focal adhesion and TAZ suppression, while restoring epithelial junction integrity. These insights provide a mechanistic rationale for the antifibrotic potential of microtubule-targeting compounds and highlight benzimidazoles as promising candidates for translational development.