ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Ethnopharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1661050
Exploring the Mechanism of Qingre Yishen Xiaozheng Formula in Treating Diabetic Kidney Disease via the HIF-1α/HO-1 Signaling Pathway: An Integrated Network Pharmacology and Experimental Study
Provisionally accepted- 1Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, China
- 2Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital, Beijing, China
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Ethnopharmacological relevance:The Qingre Yishen Xiaozheng Formula (QRYSXZF) is a traditional Chinese medicine prescription developed based on the "clearing heat and resolving stasis" principle, clinically applied for the treatment of diabetic kidney disease (DKD). Aim of the study:To investigate the therapeutic effects of QRYSXZF on DKD and elucidate its underlying mechanisms through integrated network pharmacology and experimental validation, focusing on the HIF-1α/HO-1 signaling pathway and ferroptosis regulation. Materials and methods:Active components of QRYSXZF were screened using the TCMSP database (OB ≥30%, DL ≥ 0.18), and a herb-compound-target network was constructed via Cytoscape 3.8.0. DKD-related targets were retrieved from GeneCards, OMIM, and TTD databases. Protein-protein interaction (PPI) networks, GO/KEGG enrichment analyses, and molecular docking (PyMOL/AutoDock) were performed to predict core targets and pathways. In vivo, a DKD rat model was established by unilateral nephrectomy combined with streptozotocin (STZ) injection, followed by 12-week QRYSXZF treatment. Renal function markers (BUN, 24h-UTP, KIM-1, NGAL), oxidative stress (SOD, MDA, GSH-Px), iron metabolism (SI, SF, TF), and ferroptosis-related proteins (GPX4, ACSL4, FTH1, NCOA4) were analyzed. Histopathological changes were assessed by H&E, PAS, and Masson staining, while HIF-1α/HO-1 pathway activity was evaluated via Western blot. Results:Network pharmacology identified 153 shared targets between QRYSXZF and DKD, with quercetin, kaempferol, and β-sitosterol as core active components, while KEGG analysis highlighted the HIF-1 signaling pathway as a key mechanism. In DKD rats, QRYSXZF significantly improved renal function by reducing BUN, Cys-C, KIM-1 and NGAL, attenuated oxidative stress through increasing SOD/GSH-Px and decreasing MDA, regulated iron metabolism by lowering SF and elevating TF, suppressed ferroptosis via upregulating GPX4/FTH1 and downregulating ACSL4/NCOA4, and inhibited HIF-1α/HO-1 pathway activation, with molecular docking confirming stable binding between QRYSXZF components and HIF1A/HMOX1. Conclusion:QRYSXZF alleviates DKD progression by modulating the HIF-1α/HO-1 pathway to reduce ferroptosis, oxidative stress, and iron overload, providing a scientific basis for its clinical application in DKD management.
Keywords: Qing-Re-Yi-Shen-Xiao-Zheng formula, Diabetic kidney disease, Network Pharmacology, ferroptosis, HIF-1a/HO-1 signalling pathway
Received: 07 Jul 2025; Accepted: 01 Sep 2025.
Copyright: © 2025 Han, Shou, Wang, Tian, Zheng, Liu and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Lanying Liu, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, China
Wei Jing Liu, Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital, Beijing, China
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