Hepatic thyroid hormone receptor-β signalling: Mechanisms and recent advancements in the treatment of metabolic dysfunction-associated steatohepatitis

The pharmacotherapy of metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, the metabolic dysfunction-associated steatohepatitis (MASH), remains a hot topic in research and a largely unmet need in clinical practice. As the first approval of a disease-specific drug, resmetirom, was regarded as a milestone for the management of this common liver disease, this comprehensive and updated review aimed to highlight the importance of the hepatic thyroid hormone (TH) receptor (THR)-beta signalling for the treatment of MASH, with a special focus on resmetirom. First, the genomic and non-genomic actions of the liver-directed THR-beta mediated mechanisms are summarized. THR-beta has a key role in hepatic lipid and carbohydrate metabolism; disruption of THR-beta signalling leads to dysmetabolism, thus promoting MASLD and possibly its progression to MASH and cirrhosis. In the clinical setting, this is translated into a significant association between primary hypothyroidism and MASLD, as confirmed by recent meta-analyses. An association between MASLD and subclinical intrahepatic hypothyroidism (i.e. a state of relatively low hepatic triiodothyronine concentrations, with circulating TH concentrations within the normal range) is also emerging and under investigation. In line with this, the favourable results of the phase 3 placebo-controlled MAESTRO trials led to the recent conditional approval of resmetirom by the US FDA for treating adults with MASH and moderate-to-advanced fibrosis. This conditional approval of resmetirom opened a new window to the management of this common and burdensome liver disease, thus bringing the global scientific community in front of new perspectives and challenges.