Molecular Mechanism of Dihydroquercetin in Ameliorating Metabolic Dysfunction-Associated Steatotic Liver Disease:...

Dihydroquercetin (DHQ) is a plant-derived flavonoid with well-documented antioxidant and anti-inflammatory properties. This study aimed to elucidate the therapeutic mechanisms of DHQ in metabolic dysfunction-associated steatotic liver disease (MASLD) by integrating network pharmacology with in vivo and in vitro experiments. Network pharmacology analysis identified potential DHQ targets associated with MASLD, followed by GO and KEGG enrichment analyses. A high-fat diet-induced murine MASLD model and a free fatty acid-induced HepG2 cell steatosis model were employed to evaluate the effects of DHQ. Biochemical assays, ELISA, Oil Red O staining, RT-qPCR, and Western blotting were used to assess lipid metabolism, inflammatory responses, and HIF-1 signaling. Thirty-seven overlapping targets between DHQ and MASLD were identified, with protein-protein interaction analysis highlighting key hub proteins and enrichment analyses implicating the HIF-1 signaling pathway. In vivo, DHQ significantly reduced body and liver weight, improved serum lipid profiles and liver enzyme levels, and alleviated hepatic histopathological damage. Mechanistically, DHQ activated the LKB1-AMPK axis, inhibited ACC, reduced IL-1β and TNF-α production, and attenuated aberrant HIF-1α/VEGF signaling. Consistently, DHQ decreased lipid accumulation and inflammatory cytokine expression in steatotic HepG2 cells, while CoCl₂-induced HIF-1α stabilization partially reversed these protective effects. Collectively, these findings suggest that DHQ ameliorates lipid metabolic disorders and inflammation in MASLD by modulating the HIF-1α/VEGF pathway, supporting its potential as a therapeutic candidate.