A human liver cell-based system modeling a clinical prognostic liver signature combined with single-cell RNA-Seq for discovery of liver disease therapeutics

Abstract: Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. We developed 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 NASH-HCC animal models and patient-derived tumorspheroids, we identified nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Perturbation studies combined with scRNA-Seq analyses of patient liver tissues uncovered HRH2+, CLEC5Ahigh, MARCOlow liver macrophages and hepatocytes as nizatidine targets. The PLS model combined with scRNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention. We performed bulk RNA sequencing of DMSO differentiated Huh751 at different time points