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Macrophage\u2010driven inflammation is a key contributor to diabetic kidney disease (DKD). This study aimed to determine whether PF mitigates DKD by regulating macrophage polarization. The db\/db mice were treated orally with PF (50 or 100\u2009mg\/kg\/day) for 10\u2009weeks. Renal function, histopathology, and macrophage infiltration were assessed. In\u00a0vitro, RAW264.7 macrophages were exposed to high glucose. Network pharmacology, molecular docking, cellular thermal shift assays (CETSA), and HIF\u20101\u03b1 siRNA knockdown were used to investigate mechanistic targets. PF improved renal function, reduced albuminuria, and attenuated glomerular injury. It decreased CD68\n                    <jats:sup>+<\/jats:sup>\n                    macrophage infiltration and inhibited M1 polarization, lowering TNF\u2010\u03b1 and iNOS expression. PF directly bound and stabilized HIF\u20101\u03b1, while HIF\u20101\u03b1 knockdown abolished PF's anti\u2010inflammatory effects. PF reduced HIF\u20101\u03b1 protein expression without affecting mRNA expression, indicating post\u2010transcriptional regulation. PF protects against DKD by inhibiting HIF\u20101\u03b1\u2013mediated M1 macrophage polarization, revealing a novel mechanism to modulate macrophage\u2010driven renal inflammation and supporting PF as a potential therapeutic agent for DKD.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70118","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T03:59:35Z","timestamp":1763524775000},"page":"213-226","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Paeoniflorin Attenuates the Progression of Diabetic Kidney Disease by Regulating Macrophage Differentiation"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1404-8521","authenticated-orcid":false,"given":"Chunru","family":"Shi","sequence":"first","affiliation":[{"name":"Senior Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 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Traditional Chinese Medicine Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilun","family":"Qu","sequence":"additional","affiliation":[{"name":"Senior Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases Chinese PLA General Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Liu","sequence":"additional","affiliation":[{"name":"Senior Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases Chinese PLA General Hospital  Beijing 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