Modeling Fibrosis with MASH Patient Liver-Derived Organoids.

Liu, A.; Haseman, D.; Bantu, K.; Nong, J.; Muzykantov, V.; Melamed, J.; Kegel, M.; Muscat-Rivera, J.; Weissman, D.; Smith, D.; Zhang, M.; Rader, D. J.; Raabe, T. D.

doi:10.1101/2025.09.18.677209

bioRxiv · 10.1101/2025.09.18.677209

Modeling Fibrosis with MASH Patient Liver-Derived Organoids.

Liu, A.·Haseman, D.·Bantu, K.·Nong, J.·Muzykantov, V.·Melamed, J.·Kegel, M.·Muscat-Rivera, J.·Weissman, D.·Smith, D.·Zhang, M.·Rader, D. J.·Raabe, T. D.

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Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) can lead to liver fibrosis and cirrhosis ultimately leading to liver transplantation or death. Therapeutic options for MASH-associated fibrosis are limited in part because of the lack of good model systems. To address this challenge, we developed a 3D MASH liver fibrosis model by using organoids derived from MASH patient liver co-cultured with human liver-derived hepatic stellate cells (HSC) and human peripheral blood monocytes (MC). Spontaneous self-assembly resulted in fibrotic scar-like 3D structures with senescent parenchymal cells, proliferating collagen secreting myofibroblasts (MFB) and proinflammatory TREM2+ scar-associated macrophages (MP). Single cell RNA sequencing suggested high similarity with MASH patient liver fibrotic scars. Lipid nanoparticles (LNPs) formulated with anti-YAP1siRNA could specifically and efficiently knockdown YAP1 in the MFBs, resulting in MFB senescence, a desirable therapeutic goal. This MASH patient liver-derived fibrosis model opens novel avenues towards testing treatments for MASH-associated liver fibrosis with reduced adverse effects.

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Liu, A., Haseman, D., Bantu, K., Nong, J., Muzykantov, V., Melamed, J., Kegel, M., Muscat-Rivera, J., Weissman, D., Smith, D., Zhang, M., Rader, D. J., Raabe, T. D.. 2025-09-21. Modeling Fibrosis with MASH Patient Liver-Derived Organoids.. https://doi.org/10.1101/2025.09.18.677209

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