PPARα Emerges as a Target in Lean MASLD : Acta Pharm Sin B | Jun 2026

Introduction:

Metabolic dysfunction-associated steatotic liver disease (MASLD) is traditionally linked to obesity, but an increasing number of patients develop significant hepatic steatosis despite having a normal body mass index. This entity, known as lean MASLD, presents a clinical paradox because affected individuals remain at substantial risk for progressive fibrosis, cardiovascular complications, and liver-related mortality. The mechanisms driving disease progression in this population are distinct and incompletely understood.

Problem Statement:

Unlike obesity-associated MASLD, lean MASLD cannot be fully explained by excess body weight alone. Factors such as visceral adiposity, dietary exposures, genetic susceptibility, and metabolic dysfunction contribute to disease development. Identifying the molecular pathways underlying lean MASLD is essential for developing targeted therapies tailored to this unique patient population.

Summary:

This review highlights peroxisome proliferator-activated receptor alpha (PPARα) as a central regulator in the pathogenesis of lean MASLD. PPARα plays a critical role in hepatic fatty acid oxidation, ketogenesis, and anti-inflammatory signaling, helping maintain metabolic homeostasis within the liver. The authors describe how multiple mechanisms—including aging-related signaling pathways, fructose-induced epigenetic changes, gut–liver axis disturbances, lipotoxicity, and genetic predisposition—converge to suppress PPARα activity, even in the absence of obesity. This impairment contributes to hepatic lipid accumulation and progressive metabolic dysfunction. The review further explores the limitations of currently available synthetic PPARα agonists in lean MASLD and highlights growing interest in natural product–derived modulators that simultaneously influence interconnected nuclear receptor pathways, including FXR and LXR. Particular attention is given to the PPARα–FGF21–ketogenesis axis as a key metabolic network with therapeutic potential. The authors propose that future treatment strategies should focus on selective hepatic reactivation of PPARα combined with biomarker-driven and genotype-guided patient selection. Overall, this review positions PPARα as a promising therapeutic target in lean MASLD and underscores the need for precision medicine approaches that recognize the distinct biological mechanisms underlying steatotic liver disease in non-obese individuals.