Author information

¹Institute for Regeneration & Repair, University of Edinburgh, Edinburgh, UK.

²Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK.

³Liver Unit and NIHR Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

⁴Edinburgh Pathology, University of Edinburgh, Edinburgh, UK.

⁵NAFLD Research Centre, Division of Gastroenterology and Hepatology, UC San Diego School of Medicine, La Jolla, CA, USA.

⁶Fibrosis Research Group, Newcastle University, Newcastle, UK. derek.mann@newcastle.ac.uk.

⁷Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey. derek.mann@newcastle.ac.uk.

⁸Institute for Regeneration & Repair, University of Edinburgh, Edinburgh, UK. Jonathan.Fallowfield@ed.ac.uk.

Abstract

Nonalcoholic steatohepatitis (NASH) might soon become the leading cause of end-stage liver disease and indication for liver transplantation worldwide. Fibrosis severity is the only histological predictor of liver-related morbidity and mortality in NASH identified to date. Moreover, fibrosis regression is associated with improved clinical outcomes. However, despite numerous clinical trials of plausible drug candidates, an approved antifibrotic therapy remains elusive. Increased understanding of NASH susceptibility and pathogenesis, emerging human multiomics profiling, integration of electronic health record data and modern pharmacology techniques hold enormous promise in delivering a paradigm shift in antifibrotic drug development in NASH. There is a strong rationale for drug combinations to boost efficacy, and precision medicine strategies targeting key genetic modifiers of NASH are emerging. In this Perspective, we discuss why antifibrotic effects observed in NASH pharmacotherapy trials have been underwhelming and outline potential approaches to improve the likelihood of future clinical success.