Atraric Acid Mitigates Mitochondrial Dysfunction and Inflammation via AMPKα–PGC-1α Signaling in Metabolic-Associated Fatty Liver Disease

Background: Metabolic-associated fatty liver disease (MASLD) is a leading cause of chronic liver injury worldwide, characterized by hepatic lipid accumulation, oxidative stress, inflammation, and mitochondrial dysfunction. Despite its prevalence, no approved pharmacological treatments currently exist. Atraric acid (AA), a natural compound with antioxidant and anti-inflammatory properties, has not been previously investigated in MASLD. Objective: This study aimed to evaluate the therapeutic potential of AA and elucidate its underlying mechanisms in MASLD. Methods: MASLD was modeled in mice using a high-fat diet and in alpha mouse liver 12 hepatocytes using oleic acid/palmitic acid. AA’s effects on liver injury, mitochondrial function, and inflammatory signaling were assessed through biochemical assays, histology, transcriptomic analysis, and mechanistic studies involving adenosine 5′-monophosphate-activated protein kinase (AMPK) inhibition and liver-specific AMPK knockout models. Results: AA significantly improved hepatic steatosis, reduced serum alanine transaminase and aspartate aminotransferase levels, and alleviated inflammation in MASLD mice. In vitro , AA restored mitochondrial membrane potential, enhanced adenosine triphosphate production, and suppressed reactive oxygen species accumulation and NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome activation. Mechanistically, AA directly interacted with AMPK, promoted its phosphorylation, and upregulated peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α), thereby improving mitochondrial biogenesis and redox balance. These protective effects were abolished by AMPKα inhibition or knockout, confirming AMPK as a key mediator. Additionally, AA modulated related pathways, including SIRT1 and mTOR, suggesting broader metabolic benefits. Conclusion: AA mitigates MASLD by activating the AMPK–PGC-1α axis, restoring mitochondrial function, and reducing ROS-driven inflammation. These findings highlight AA as a promising candidate for MASLD therapy and warrant further clinical investigation. Antioxid. Redox Signal. 44, 332–356.