Resveratrol alleviates glucolipid metabolism disorders in diabetic nephropathy via the HIF-1α pathway: a network pharmacology and experimental validation study
Abstract
BackgroundDiabetic nephropathy (DN) represents a major microvascular complication of diabetes with complex pathogenesis. Resveratrol (RSV), a polyphenol from Polygonum cuspidatum, is a potential therapeutic agent for DN. However, the exact mechanisms of RSV modulating glucolipid metabolism in DN remain unclear.MethodsPotential targets and signaling pathways of RSV against DN were predicted by network pharmacology and molecular docking. Based on the prediction, a DN model was generated in male Wistar rats using a high-fat diet/streptozotocin (HFD/STZ) induction, followed by 12-week RSV (30 mg/kg/d) for in vivo validation. In vitro, HK-2 cells cultured in palmitic acid (PA) were treated with either RSV or LW6, a hypoxia-inducible factor 1α (HIF-1α) inhibitor. Biochemical parameters, histopathological alterations and lipid deposition were examined. AKT/HIF-1α pathway activation and downstream metabolic gene levels were analyzed via Western blot, immunofluorescence and RT-qPCR.ResultsBioinformatics findings revealed RSV exerts its anti-DN effects predominantly through the prioritized candidate AKT1 and the highly enriched HIF-1 signaling pathway. In vivo, RSV significantly ameliorated hyperglycemia and renal dysfunction and alleviated histopathological injuries and glycogen storage. Mechanistically, RSV suppressed p-AKT and HIF-1α expression, reduced Glut1 mRNA levels, and elevated Ldlr mRNA levels, significantly. In vitro, RSV effectively decreased lipid accumulation and inhibited HIF-1α expression, downregulating SREBP1, SREBP2, LDLR, GLUT1 and TGF-β1 and upregulating INSIG2. The effects of LW6 were largely consistent with those of RSV but failed to reduce HIF-1α mRNA levels.ConclusionThe attenuation of glucolipid metabolic disorders in DN by RSV is associated with suppression of the HIF-1α pathway, highlighting the therapeutic potential of RSV for DN.
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BibTeX
@article{li2026resveratrol,
title = {{Resveratrol alleviates glucolipid metabolism disorders in diabetic nephropathy via the HIF-1α pathway: a network pharmacology and experimental validation study}},
author = {Siyun Li and Dongxin Lyu and Fuzhen Feng and Runhua Zhou and Jinping Zhang and Yanhui Deng},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1971426},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1971426},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Resveratrol alleviates glucolipid metabolism disorders in diabetic nephropathy via the HIF-1α pathway: a network pharmacology and experimental validation study
AU - Siyun Li
AU - Dongxin Lyu
AU - Fuzhen Feng
AU - Runhua Zhou
AU - Jinping Zhang
AU - Yanhui Deng
PY - 2026
DA - 2026/10/30
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1971426
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1971426
AB - BackgroundDiabetic nephropathy (DN) represents a major microvascular complication of diabetes with complex pathogenesis. Resveratrol (RSV), a polyphenol from Polygonum cuspidatum, is a potential therapeutic agent for DN. However, the exact mechanisms of RSV modulating glucolipid metabolism in DN remain unclear.MethodsPotential targets and signaling pathways of RSV against DN were predicted by network pharmacology and molecular docking. Based on the prediction, a DN model was generated in male Wistar rats using a high-fat diet/streptozotocin (HFD/STZ) induction, followed by 12-week RSV (30 mg/kg/d) for in vivo validation. In vitro, HK-2 cells cultured in palmitic acid (PA) were treated with either RSV or LW6, a hypoxia-inducible factor 1α (HIF-1α) inhibitor. Biochemical parameters, histopathological alterations and lipid deposition were examined. AKT/HIF-1α pathway activation and downstream metabolic gene levels were analyzed via Western blot, immunofluorescence and RT-qPCR.ResultsBioinformatics findings revealed RSV exerts its anti-DN effects predominantly through the prioritized candidate AKT1 and the highly enriched HIF-1 signaling pathway. In vivo, RSV significantly ameliorated hyperglycemia and renal dysfunction and alleviated histopathological injuries and glycogen storage. Mechanistically, RSV suppressed p-AKT and HIF-1α expression, reduced Glut1 mRNA levels, and elevated Ldlr mRNA levels, significantly. In vitro, RSV effectively decreased lipid accumulation and inhibited HIF-1α expression, downregulating SREBP1, SREBP2, LDLR, GLUT1 and TGF-β1 and upregulating INSIG2. The effects of LW6 were largely consistent with those of RSV but failed to reduce HIF-1α mRNA levels.ConclusionThe attenuation of glucolipid metabolic disorders in DN by RSV is associated with suppression of the HIF-1α pathway, highlighting the therapeutic potential of RSV for DN.
SN - 1663-9812
ER -