Abstract

BACKGROUND Atraric acid (AA) is a secondary metabolite of lichen with anti-inflammatory and antioxidant properties, however, its specific mechanism in the high-fat diet (HFD) is not yet clear. Unc-51-like kinase 1 (ULK1) is a serine/threonine kinase that plays a central role in autophagy, mitochondrial quality control, and inflammation. OBJECTIVE This stiudy aims to investigate the protective mechanism of AA against HFD-induced spleen injury through the ULK1 pathway. MATERIALS AND METHODS The in vivo mice models of spleen injury induced by HFD and the in vitro high-fat J774A.1 macrophages model induced by OA/PA were established. The effects and mechanisms of AA were evaluated through histopathological examination, real-time fluorescence quantitative PCR, biochemical analysis, immunoblotting, ELISA, etc. RESULTS: Results showed that, compared with the HFD, AA ameliorated splenic histopathology, restoring a sharp demarcation between red and white pulp. AA treatment lowered the pro-inflammatory mediators (TNF-α, IL-1β, IL-6, iNOS) while elevating the anti-inflammatory cytokine IL-10. In parallel, AA raised the antioxidant indices (CAT, GSH, T-AOC) and reduced lipid-peroxidation product MDA. Mechanistically, AA down-regulated cytoplasmic mtDNA (non-numt, D-loop, and Cox1) and restored mitochondrial ATP. Further investigation revealed that these protective effects were dependent on AA-induced ULK1 phosphorylation at Ser555; activating this site was necessary to suppress pro-inflammatory cytokines and cytosolic mtDNA, enhance IL-10, and bolster antioxidant capacity. CONCLUSIONS