Selective PPARα Modulator (SPPARMα) in the Era of the MASLD Pandemic: Current Insights and Future Prospects.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a significant global health concern, affecting approximately 30% of the population. In Japan, its prevalence is also rising rapidly and is expected to reach 50% by 2040. This situation can be described as a "MASLD pandemic", emphasizing the urgent need for effective therapeutic interventions. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that play essential roles in lipid metabolism, inflammation regulation, and fibrosis modulation. Among them, PPARα is a key regulator of lipid homeostasis, primarily expressed in the liver and other metabolically active tissues. Its activation promotes fatty acid oxidation and improves lipid profiles, making it a crucial target for metabolic disorders. In Japan, a novel selective PPARα modulator (SPPARMα) was developed as a lipid-lowering agent for treating dyslipidemia. Over time, increasing clinical evidence has suggested that SPPARMα has beneficial effects on MASLD patients' liver function. This review aims to summarize the therapeutic potential of SPPARMα in MASLD by examining the functional mechanisms of PPARα, preclinical studies in animal models, and accumulating clinical evidence from MASLD patients. Furthermore, we provide an overview of ongoing clinical trials investigating SPPARMα for MASLD treatment.