The thyroid-liver axis in MASLD: From metabolic control to clinical translation

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver diseases worldwide, with growing incidence paralleling the rise in clinical and economic burden. Recently, resmetirom has emerged as the first approved pharmacotherapy for metabolic dysfunction-associated liver steatohepatitis (MASH) with fibrosis, partially mimicking thyroid hormone (TH) actions in the liver with good safety and promising therapeutic potential. The thorough understanding of hepatic TH availability and signaling, exerting pleiotropic actions in several key biological processes including lipid homeostasis, enabled this breakthrough in hepatology. Here, we summarize current knowledge on the thyroid signaling axis and, in particular, its role in regulating lipid metabolism in the liver in both healthy and pathological conditions. We discuss the development of thyromimetics, initially as lipid-lowering drugs and further as hepatic lipid-clearing therapies against MASH, permitted by achieving TH receptor β selectivity and liver specificity, and analyze results from clinical trials while awaiting long-term outcome data.