Despite significant challenges impeding the development of effective pharmacotherapies for NASH, three agents, obeticholic acid, resmetirom, and the peroxisome proliferator-activated receptor (PPAR) agonist lanifibranor, have entered phase III of their trials. As guidance for NASH drug development, the Food and Drug Administration and European Medicines Agency have identified substantial histological improvement, i.e. resolution of NASH and/or improvement in fibrosis stage in sequential liver biopsies, as a surrogate marker reasonably likely to yield drug approval and long-term benefit. This emphasis on inflammation and fibrosis supports the development of anti-inflammatory and/or anti-fibrotic targets for NASH.
This review aims to present an integrated view of anti-inflammatory and antifibrotic strategies for the treatment of NASH.
Metabolic injury to the liver triggers inflammatory processes that drive the progression of NASH and liver fibrosis. As such, metabolism, inflammation, and fibrosis are intricately interconnected, which warrants the development of pharmacotherapies simultaneously targeting multiple NASH-associated molecular pathways or cellular components. Pharmacologic strategies with the potential to attenuate metabolic dysregulation and cell injury in NASH include genetic variant modification (e.g. PNPLA3 gene silencing) and/or targeting nuclear receptor agonists as well as modulators of lipotoxicity. Agents targeting extrahepatic inflammatory signals from the gut, endocrine system, or adipose tissue are also currently under investigation. Conversely, anti-inflammatory and -fibrotic strategies for NASH include blunting immune cell activation, recruitment, and responses for the former, and inhibiting hepatic stellate cell activation for the latter. Emerging therapeutic approaches to NASH resolution rely on cell therapy via individualised and reprogrammed macrophages [‘CAR-iMac’] or immune-regulatory mesenchymal stromal cells.