A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery

Crouchet et al.▾ Crouchet, E., Bandiera, S., Fujiwara, N., Li, S., El Saghire, H., Fernández-Vaquero, M., Riedl, T., Sun, X., Hirschfield, H., Jühling, F., Zhu, S., Roehlen, N., Ponsolles, C., Heydmann, L., Saviano, A., Qian, T., Venkatesh, A., Lupberger, J., Verrier, E.R., Sojoodi, M., Oudot, M.A., Duong, F.H.T., Masia, R., Wei, L., Thumann, C., Durand, S.C., González-Motos, V., Heide, D., Hetzer, J., Nakagawa, S., Ono, A., Song, W.-M., Higashi, T., Sanchez, R., Kim, R.S., Bian, C.B., Kiani, K., Croonenborghs, T., Subramanian, A., Chung, R.T., Straub, B.K., Schuppan, D., Ankavay, M., Cocquerel, L., Schaeffer, E., Goossens, N., Koh, A.P., Mahajan, M., Nair, V.D., Gunasekaran, G., Schwartz, M.E., Bardeesy, N., Shalek, A.K., Rozenblatt-Rosen, O., Regev, A., Felli, E., Pessaux, P., Tanabe, K.K., Heikenwälder, M., Schuster, C., Pochet, N., Zeisel, M.B., Fuchs, B.C.*, Hoshida, Y.*, Baumert, T.F.*

Nature Communications , Volume 12

March, 2023

Abstract

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2⁺, CLEC5A^high, MARCO^lowliver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.