Advancements in pharmacological treatment of NAFLD/MASLD: a focus on metabolic and liver-targeted interventions Non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) are increasingly prevalent, with NAFLD affecting 30% of adults globally. These conditions are closely associated with obesity and type 2 diabetes (T2DM). Recent advancements in pharmacological treatments for NAFLD/MASLD include repurposing drugs originally targeting T2DM and obesity, such as pioglitazone, GLP1 receptor agonists (liraglutide, semaglutide), multi-agonists (tirzepatide, retatrutide), and SGLT2 inhibitors. Additionally, drugs specifically targeting NAFLD/MASLD, such as resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, are in Phase 3 clinical trials. Pioglitazone, a PPARγ agonist, improves insulin resistance and reduces liver fat. However, it has significant side effects. A deuterium-stabilized enantiomer of pioglitazone (PXL065) showed improved liver fat reduction and no weight gain in clinical trials. GLP1 receptor agonists, such as liraglutide and semaglutide, have shown efficacy in reducing liver fat and improving NASH. Tirzepatide, a dual GIP/GLP1 agonist, has shown superior results in reducing liver fat and improving metabolic parameters. SGLT2 inhibitors have also shown benefits in reducing liver fat and improving metabolic outcomes. Resmetirom, a TRβ agonist, has shown significant improvements in liver fat reduction and NASH resolution in clinical trials. Fibroblast growth factor 21 analogs, such as efruxifermin and pegozafermin, are in Phase 3 trials and show promise in improving fibrosis and NASH. Lanifibranor, a PPAR agonist, has shown significant improvements in NASH resolution and fibrosis improvement in clinical trials. The development of these drugs is guided by regulatory agencies, which require specific endpoints for approval. The FDA and EMA have different requirements for conditional approval. The use of liver biopsy for diagnosis is limited due to its invasiveness and variability in results. Non-invasive methods are being explored to assess treatment response. Combination therapy may be beneficial for NAFLD/MASLD, as it can target multiple pathways and improve outcomes. Drugs targeting underlying metabolic abnormalities may be more effective in early stages of the disease, while liver-targeted drugs may be more effective in advanced stages with significant inflammation and fibrosis. The approval of the first treatments for NAFLD/MASLD is likely near, with several drugs in Phase 3 trials. The future of NAAdvancements in pharmacological treatment of NAFLD/MASLD: a focus on metabolic and liver-targeted interventions Non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) are increasingly prevalent, with NAFLD affecting 30% of adults globally. These conditions are closely associated with obesity and type 2 diabetes (T2DM). Recent advancements in pharmacological treatments for NAFLD/MASLD include repurposing drugs originally targeting T2DM and obesity, such as pioglitazone, GLP1 receptor agonists (liraglutide, semaglutide), multi-agonists (tirzepatide, retatrutide), and SGLT2 inhibitors. Additionally, drugs specifically targeting NAFLD/MASLD, such as resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, are in Phase 3 clinical trials. Pioglitazone, a PPARγ agonist, improves insulin resistance and reduces liver fat. However, it has significant side effects. A deuterium-stabilized enantiomer of pioglitazone (PXL065) showed improved liver fat reduction and no weight gain in clinical trials. GLP1 receptor agonists, such as liraglutide and semaglutide, have shown efficacy in reducing liver fat and improving NASH. Tirzepatide, a dual GIP/GLP1 agonist, has shown superior results in reducing liver fat and improving metabolic parameters. SGLT2 inhibitors have also shown benefits in reducing liver fat and improving metabolic outcomes. Resmetirom, a TRβ agonist, has shown significant improvements in liver fat reduction and NASH resolution in clinical trials. Fibroblast growth factor 21 analogs, such as efruxifermin and pegozafermin, are in Phase 3 trials and show promise in improving fibrosis and NASH. Lanifibranor, a PPAR agonist, has shown significant improvements in NASH resolution and fibrosis improvement in clinical trials. The development of these drugs is guided by regulatory agencies, which require specific endpoints for approval. The FDA and EMA have different requirements for conditional approval. The use of liver biopsy for diagnosis is limited due to its invasiveness and variability in results. Non-invasive methods are being explored to assess treatment response. Combination therapy may be beneficial for NAFLD/MASLD, as it can target multiple pathways and improve outcomes. Drugs targeting underlying metabolic abnormalities may be more effective in early stages of the disease, while liver-targeted drugs may be more effective in advanced stages with significant inflammation and fibrosis. The approval of the first treatments for NAFLD/MASLD is likely near, with several drugs in Phase 3 trials. The future of NA