Vorinostat Can Reduce an Ongoing Fibrosis and Preserve Key Liver Metabolic Functions by Selectively Altering Mesenchymal Cell Differentiation

Vorinostat (SAHA) reduced established, ongoing liver fibrosis in a human iPSC-derived hepatic micro-organoid model and preserved ammonia detoxification and CYP3A4-mediated drug metabolism.

• Why it matters: Predictive human in vitro models for anti-fibrotic therapy are limited, slowing targeted drug discovery for fibrosis driven by activated hepatic stellate cells.
• What they did: The study built a collagen-labeling microHO fibrosis model, screened drugs under prophylactic TGF{beta}1, then used single-cell RNA sequencing and CRISPR-Cas12a lineage tracing to test Vorinostat’s mechanism.
• The result: Vorinostat redirected HSC differentiation away from pro-fibrotic MyoFs toward a fibrosis-suppressing MesInh cell by reversing TGF{beta}1-induced epigenetic silencing, enabling metabolic gene expression and anti-fibrotic effectors that neutralize ongoing TGF{beta}1 signaling.

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