{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T11:56:21Z","timestamp":1784894181207,"version":"3.55.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Ethnopharmacological relevance<\/jats:title><jats:p>The Qingre Yishen Xiaozheng Formula (QRYSXZF) is a traditional Chinese medicine prescription developed based on the \u201cclearing heat and resolving stasis\u201d principle, clinically applied for the treatment of diabetic kidney disease (DKD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim of the study<\/jats:title><jats:p>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-1\u03b1\/HO-1 signaling pathway and ferroptosis regulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Active components of QRYSXZF were screened using the TCMSP database (OB \u2265 30%, DL \u2265 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. <jats:italic>In vivo<\/jats:italic>, 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&amp;amp;E, PAS, and Masson staining, while HIF-1\u03b1\/HO-1 pathway activity was evaluated via Western blot.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Network pharmacology identified 153 shared targets between QRYSXZF and DKD, with quercetin, kaempferol, and \u03b2-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-1\u03b1\/HO-1 pathway activation, with molecular docking confirming stable binding between QRYSXZF components and HIF1A\/HMOX1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>QRYSXZF alleviates DKD progression by modulating the HIF-1\u03b1\/HO-1 pathway to reduce ferroptosis, oxidative stress, and iron overload, providing a scientific basis for its clinical application in DKD management.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1661050","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T05:31:59Z","timestamp":1758864719000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Exploring the mechanism of Qingre Yishen Xiaozheng formula in treating diabetic kidney disease via the HIF-1\u03b1\/HO-1 signaling pathway: an integrated network pharmacology and experimental study"],"prefix":"10.3389","volume":"16","author":[{"given":"Fei","family":"Han","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieyu","family":"Shou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoxian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhejing","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijuan","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"35","DOI":"10.26402\/jpp.2021.1.04","article-title":"Galangin protects against oxidative damage and attenuates inflammation and apoptosis via modulation of NF-\u03baB p65 and caspase-3 signaling molecules in a rat model of diabetic nephropathy","volume":"72","author":"Aladaileh","year":"2021","journal-title":"J. physiology Pharmacol. an official J. 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