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

Area of Science:

• Hepatology
• Pharmacology
• Translational Medicine

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis incidence is rising, with limited treatment options.
• Many potential MASH therapeutics fail in clinical trials despite preclinical promise.
• Predicting therapeutic efficacy early is crucial for MASH drug development.

Purpose of the Study:

• To evaluate a fibrogenic gene signature for predicting MASH therapeutic efficacy.
• To assess the anti-fibrotic potential of obeticholic acid, cenicriviroc, and pioglitazone in a preclinical MASH model.
• To validate early gene expression predictions against long-term histological fibrosis endpoints.

Main Methods:

• Induction of MASH and obesity in Ldlr-/-.Leiden mice using a high-fat diet (HFD).
• Short-term (4-week) treatment with obeticholic acid, cenicriviroc, and pioglitazone.
• Evaluation of a fibrogenic gene signature to predict profibrotic processes.
• Comparison of gene signature predictions with long-term histological fibrosis outcomes.

Main Results:

• Cenicriviroc and pioglitazone showed no impact on the fibrogenic gene signature or histological fibrosis.
• Obeticholic acid significantly improved the fibrogenic gene signature, aligning with long-term fibrosis reduction.
• Early gene expression changes accurately predicted the long-term efficacy of tested therapeutics.

Conclusions:

• A fibrogenic gene signature can serve as an early screening tool for MASH therapeutics.
• Short-term studies using this signature can rapidly assess drug efficacy on liver fibrosis.
• This approach aids in the translational development of novel MASH treatments.