MASH and the race for liver antifibrotics

Metabolic dysfunction-associated steatohepatitis (MASH), along with other chronic liver diseases, leads to progressive fibrosis and, ultimately, cirrhosis. Liver fibrosis is a major cause of global morbidity and mortality. Although past efforts to develop antifibrotic drugs have largely failed, recent advances in MASH metabolic therapies offer new hope. These include both indirect-acting agents such as glucagon-like peptide 1 (GLP-1) analogues, which reduce liver fat by promoting weight loss, and therapies with direct-acting mechanisms on the liver, such as thyroid hormone receptor beta (THRβ) activators and fibroblast growth factor 21 (FGF21) analogues. This perspective summarises emerging antifibrotics, from the fast-evolving class of metabolic therapies through to the more sluggish development of non-metabolic antifibrotics. We consider future therapeutic combinations and patient stratifiers that may impact patient outcomes, and close by asking if fibrosis reversal should be the only goal.