@article{Wang2026, 
author = {Lupeng Wang and Ying Ni and Panpan Han and Chao Chen and Xuefang Wang and Ling Chen and Feifei Li and Zhiyong He and Wensheng Zhang},
title = {Lithocholic Acid Ameliorates Diabetic Nephropathy by Suppressing the AGEs/RAGE Signaling Pathway and Modulating Inflammation, Endoplasmic Reticulum Stress, and Lipid Metabolism},
year = {2026},
journal = {Food Science and Human Wellness},
keywords = {Diabetic nephropathy, Licochalcone A, Lipid metabolism, AGEs/RAGE, Inflammation, Endoplasmic reticulum stress},
url = {https://www.sciopen.com/article/10.26599/FSHW.2026.9251171},
doi = {10.26599/FSHW.2026.9251171},
abstract = {Diabetic nephropathy (DN) is a leading cause of end-stage renal disease, and the advanced glycation end products (AGEs) and their receptor RAGE play a critical pathogenic role in DN progression. This study investigated the therapeutic mechanisms of licochalcone A (LCA), a bioactive flavonoid from licorice, against DN with emphasis on AGEs/RAGE signaling modulation. Male C57BL/6J mice were used to establish a high-fat diet/streptozotocin-induced DN model, followed by 4-week treatment with LCA (5, 10, 20 mg/kg/day) or metformin (250 mg/kg/day). LCA treatment significantly improved glucose tolerance, reduced fasting blood glucose levels, and ameliorated characteristic renal pathological changes including mesangial matrix expansion and collagen deposition. Mechanistically, LCA suppressed AGEs accumulation in both serum and renal tissues while downregulating RAGE expression, thereby attenuating NF-κB-mediated inflammatory responses (TNF-α, IL-1β, IL-6). Furthermore, LCA mitigated oxidative stress by restoring SOD activity and reducing MDA and ROS levels, and alleviated endoplasmic reticulum stress through suppression of the GRP78/PERK/ATF4/CHOP pathway, consequently reducing renal cell apoptosis. Serum metabolomics revealed that LCA corrected lipid metabolism disorders, with KEGG enrichment analysis highlighting ABC transporter pathway involvement. LCA treatment reversed diabetic dyslipidemia, prevented ectopic lipid accumulation in kidneys, and modulated the SREBP-1c/ABCA1 axis. These findings were validated in high glucose-treated HK-2 cells. In conclusion, LCA demonstrates multi-targeted nephroprotective effects in DN through suppression of AGEs/RAGE signaling and downstream modulation of inflammation, oxidative stress, endoplasmic reticulum stress, and lipid metabolism dysregulation.}
}