Pan-PPAR agonists: emerging therapeutic strategies for metabolic dysfunction-associated steatotic liver disease.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), has emerged as a leading global chronic liver disorder, affecting approximately 30% of the general population. Characterized by the presence of hepatic steatosis along with at least one metabolic comorbidity, MASLD represents a progressive disease spectrum ranging from simple steatosis to hepatocellular carcinoma. The pathogenesis of MASLD involves a complex interplay of metabolic dysregulation, insulin resistance, oxidative stress, and inflammation, which remains incompletely elucidated. Peroxisome proliferator-activated receptors (PPARs) are core lipid and metabolic sensors that orchestrate the transcriptional regulation of glucose homeostasis, lipid metabolism, adipogenesis, and anti-inflammatory responses, making them pivotal therapeutic targets in MASLD. While selective or dual PPAR agonists have reached efficacy plateaus and raised safety concerns in clinical trials, pan-PPAR agonists coordinated activation of all three PPAR isoforms with broader therapeutic efficacy and improved safety profiles. This review delineates the biological rationale for PPAR modulation in MASLD, critically evaluates current preclinical and clinical evidence for pan-PPAR agonists, and discusses emerging strategies for optimizing their development as comprehensive therapeutic interventions for MASLD.