Luigi Elio Adinolfi, Aldo Marrone, Antonio Izzi, Antonio Craxı̀
INTRODUCTION: Resmetirom and semaglutide are the first drugs to be approved for the pharmacological treatment of metabolic-associated steatohepatitis (MASH) and moderate-to-severe liver fibrosis. However, approval was based on histological endpoints obtained during a relatively short trial period, leaving some important questions unanswered. AREAS COVERED: Resmetirom acts directly on the liver by activating thyroid hormone receptor β. Semaglutide acts systemically, reducing weight and improving metabolism. Both drugs induce resolution of MASH and improve liver fibrosis in a significant proportion of patients. The drugs are generally well tolerated, but significant gastrointestinal side effects can occur. Patient selection for treatment and efficacy evaluation should be based on noninvasive tests (NITs), but a substantial unresolved issue remains. Further issues include monitoring and the duration of treatment, as well as the impact of treatment on hepatic and systemic disease outcomes. Ensuring fair access to treatment for all is a challenge facing the global health community. EXPERT OPINION: This review explores the current approach to issues and challenges associated with using resmetirom and semaglutide in patients with MASH, proposing reference points to assist physicians in their clinical practice. Furthermore, we emphasize the importance of implementing interventions within the healthcare system to ensure equitable access to therapies.