Metabolites derived from cell signaling pathways modulate AMPK-dependent autophagic flux in disease-relevant cell models under cellular stress conditions

Autophagy is a critical adaptive response to metabolic stress that is closely associated with AMP-activated protein kinase (AMPK) signaling. This study investigated the effects of the physiologically relevant dietary metabolites sodium acetate and resveratrol on AMPK-associated autophagic flux and oxidative stress in primary human fibroblasts, HepG2 hepatocytes, and SH-SY5Y neuroblastoma cells subjected to nutrient deprivation. Using bafilomycin A1-sensitive LC3-II turnover assays, pharmacological inhibition, and cellular ROS measurements, we found that both metabolites significantly enhanced autophagic flux in a time- and concentration-dependent manner, with maximal responses observed at 200 µM acetate and 1 µM resveratrol. Pharmacological evidence supported the involvement of AMPK signaling in these responses, which were also associated with marked reductions in mitochondrial superoxide and total intracellular ROS. Importantly, these cytoprotective effects were observed at physiologically relevant concentrations, without compromising lysosomal integrity, and were closely associated with enhanced autophagic activity rather than direct radical scavenging. Collectively, our findings suggest that sodium acetate and resveratrol may act as modulators of AMPK-associated autophagy and redox homeostasis, providing mechanistic support for their potential nutraceutical applications in metabolic and age-related disorders.