Molecular Mechanism of Dihydroquercetin in Ameliorating Metabolic Dysfunction–Associated Steatotic Liver Disease: Insights Into the HIF‐1α/VEGF Pathway

TL;DR

This study shows that dihydroquercetin (DHQ) helps reduce liver disease by targeting the HIF-1α/VEGF pathway, improving liver health and reducing inflammation.

Contribution

The study reveals a novel mechanism by which DHQ treats MASLD through the HIF-1α/VEGF pathway.

Findings

DHQ reduced body and liver weight and improved lipid profiles in a MASLD mouse model.

DHQ inhibited HIF-1α/VEGF signaling and reduced inflammation in both mice and HepG2 cells.

Blocking HIF-1α reversed DHQ's protective effects, confirming its role in the mechanism.

Abstract

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.

Dihydroquercetin (DHQ) alleviates lipid metabolic dysfunction and hepatic inflammation in MASLD. Mechanistically, DHQ modulates the HIF‐1α/VEGF signaling pathway, contributing to improved liver homeostasis.

Figures