Natural Product Treatment for Metabolic Dysfunction-Associated Steatotic Liver Disease: Targeted Mitochondrial...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by progressive mitochondrial dysfunction that disrupts hepatocellular metabolism, redox homeostasis, and inter-organelle communication. Hepatic metabolic zonation, maintained by spatially specialized mitochondrial networks, coordinates β-oxidation, oxidative phosphorylation, and lipid synthesis under physiological conditions. Chronic nutrient excess and insulin resistance disrupt this zonal organization, particularly in pericentral hepatocytes, leading to oxidative imbalance, defective mitochondrial quality control (MQC), and lipid accumulation. Mitochondrial injury is not confined to hepatocytes. The release of mitochondrial DNA (mtDNA), cardiolipin, and other mitochondrial danger-associated molecular patterns activates Kupffer cells and hepatic stellate cells through TLR9- and cGAS-STING-dependent pathways, thereby amplifying inflammatory and fibrogenic responses. Recent studies indicate that selected natural compounds improve mitochondrial function by enhancing AMPK-SIRT1-PGC-1α-dependent biogenesis, promoting PINK1/Parkin-mediated mitophagy, and attenuating mito-DAMP-driven innate immune activation. This review integrates liver metabolism and mitochondrial stress signaling pathways, elucidates the mechanistic framework of liver-mitochondrial interactions in MASLD, and explores pharmacological strategies targeting organelles to restore liver metabolic homeostasis.