Antifibrotic therapy in nonalcoholic steatohepatitis: time for a human-centric approach

TY - JOUR

T1 - Antifibrotic therapy in nonalcoholic steatohepatitis

T2 - time for a human-centric approach

AU - Brennan, Paul

AU - Elsharkawy, Ahmed M.

AU - Kendall, Timothy J.

AU - Loomba, Rohit

AU - Mann, Derek A.

AU - Fallowfield, Jonathan A.

N1 - Copyright: © 2023, Springer Nature Limited.

PY - 2023/10

Y1 - 2023/10

N2 - 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.

AB - 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.

KW - Hepatic stellate cells

KW - Liver fibrosis

KW - Non-alcoholic fatty liver disease

KW - Non-alcoholic steatohepatitis

UR - https://www.scopus.com/pages/publications/85160811711

U2 - 10.1038/s41575-023-00796-x

DO - 10.1038/s41575-023-00796-x

M3 - Article

C2 - 37268740

SN - 1759-5045

VL - 20

SP - 679

EP - 688

JO - Nature Reviews Gastroenterology & Hepatology

JF - Nature Reviews Gastroenterology & Hepatology

ER -