Unlocking the potential of THR-β agonist therapies: resmetirom's chemistry, biology, and patent insights.

Non-alcoholic steatohepatitis (NASH) is a severe manifestation of non-alcoholic fatty liver disease (NAFLD), which is characterized by hepatic steatosis, inflammation, and hepatocyte destruction. Newly adopted nomenclature, metabolic dysfunction-associated fatty liver disease (MAFLD), allows to signify the importance of metabolic dysfunction. For which the current treatment options are limited and often associated with adverse effects, creating a need for targeted therapies. This manuscript evaluates resmetirom (RMT), a selective thyroid hormone receptor (THR)-β agonist, as a promising treatment for MASH (metabolic associated steatohepatitis). The pharmacokinetic properties, synthesis pathways, and therapeutic effects of RMT were reviewed. Preclinical and clinical trials assessed the efficacy and safety of RMT at doses of 80 mg and 100 mg, with observations that included improvements in liver histology and fibrosis scores. The manuscript also explored the role of RMT in multimodal treatment strategies alongside lifestyle modifications. RMT enhances fatty acid oxidation, modulates mitophagy, and exerts potential anti-fibrotic effects, leading to improved hepatic function and reduced disease progression. Clinical trials demonstrated significant improvements in liver histology and fibrosis scores with a favorable safety profile. RMT offers therapeutic benefits with fewer side effects compared to existing treatments for advanced MASH. RMT represents a promising therapeutic option for patients with advanced MASH, offering improved outcomes and reduced adverse effects. Further studies are needed to evaluate the long-term effectiveness, affordability, and accessibility of RMT.