Atraric Acid Mitigates Mitochondrial Dysfunction and Inflammation via AMPKα-PGC-1α Signaling in Metabolic-Associated...

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.

This study aimed to evaluate the therapeutic potential of AA and elucidate its underlying mechanisms in MASLD.

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.

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.

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.