Fibrogenic Gene Signature as Early Prediction for the Efficacy of Pharmacological Interventions for MASH‐Associated Fibrosis

ABSTRACT The incidence of metabolic dysfunction‐associated steatohepatitis (MASH) and associated liver fibrosis is rapidly increasing, while pharmacological treatment options remain limited. Despite great efforts in developing novel MASH therapeutics, many investigative therapeutics that reduced fibrosis in preclinical models ultimately failed in clinical trials. To this end, we explored the possibility of predicting the efficacy of therapeutics by evaluating changes in the expression of a fibrogenic gene signature in the early stages of disease development and before effects on pathology become evident. Ldlr−/−.Leiden mice were fed a high‐fat diet (HFD) to induce obesity and MASH. Mice were subsequently treated for 4 weeks with various therapeutics with established efficacy (obeticholic acid) or lack of efficacy (cenicriviroc and pioglitazone) to study their anti‐fibrotic potential. Expression of a fibrogenic gene signature was evaluated, which predicts profibrotic processes before histopathologic fibrosis develops. The predictions were compared with a long‐term experiment reaching histological fibrosis endpoints. Cenicriviroc and pioglitazone did not affect HFD‐induced fibrosis signature, indicative of no effect of these treatments on active fibrosis processes. Consistently, in the long‐term treatment study, both cenicriviroc and pioglitazone did not affect HFD‐induced histologically measured fibrosis. In contrast, obeticholic acid improved the fibrogenic gene signature to a healthier state compared to untreated HFD controls. These early gene expression changes aligned with long‐term histological fibrosis endpoints and clinical data on these investigative therapeutics. This study highlights the potential of using short‐term studies and applying a fibrogenic gene signature as an early screening tool to investigate the efficacy of investigative drugs on MASH‐associated fibrosis. This signature, which is based on the active fibrosis processes in humans, may allow rapid screening of therapeutics, or combinations thereof, when used in a translational mouse model.