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bioRxiv · 10.1101/2025.04.29.651320

AI-assisted Drug Re-purposing for Human Liver Fibrosis

GUAN, Y.·Inchai, J.·Fang, Z.·Law, J.·Brito, A. A. G.·Pawlosky, A.·GottWeis, J.·Daryin, A.·Myaskovsky, A.·Palepu, A.·Rong, k.·Xu, Y.·Tu, T.·Peltz, G.
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Abstract

Liver fibrosis is a severe disease with few treatment options due to the poor quality of the available animal and in vitro models. To address this, we investigated whether a hypothesis generating multi-agent AI system (AI co-scientist) could assist in re-purposing drugs for treatment of liver fibrosis and direct their experimental characterization. A multi-parameter image analysis workflow, which enabled anti-fibrotic efficacy and drug toxicity to be serially assessed in multi-lineage human hepatic organoids grown in microwells (i.e., microHOs), was used to assess the effects of 14 drugs. Remarkably, two of the three AI co-scientist-recommended drugs that targeted epigenomic modifiers exhibited significant anti-fibrotic activity. Analysis of the anti-fibrotic effects of five drugs indicated that two inhibited TGF{beta}-induced intracellular signaling and three drugs altered TGF{beta}-induced mesenchymal cell differentiation. Since all five of the anti-fibrotic drugs reduced TGF{beta}-induced chromatin structural changes, epigenomic changes play an important role in the pathogenesis of liver fibrosis. One AI co-scientist recommended drug is an FDA-approved anti-cancer treatment (Vorinostat) that reduced TGF{beta}-induced chromatin structural changes by 91% and promoted liver parenchymal cell regeneration in microHOs. Hence, the use of AI co-scientist and this microHO platform identified a potential new generation of liver fibrosis treatments that also promote liver regeneration.

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GUAN, Y., Inchai, J., Fang, Z., Law, J., Brito, A. A. G., Pawlosky, A., GottWeis, J., Daryin, A., Myaskovsky, A., Palepu, A., Rong, k., Xu, Y., Tu, T., Peltz, G.. 2025-05-04. AI-assisted Drug Re-purposing for Human Liver Fibrosis. https://doi.org/10.1101/2025.04.29.651320

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