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Insulin-resistant HepG2 cells and high-fat diet induced type 2 diabetes mice are treated with DNJ, TFs, or DNJ-TFs, assessing glycolipid profiles and inflammatory markers. Network pharmacology, molecular docking, CETSA, immunofluorescence, Western blot, and Real-time PCR validate key targets, highlighting PTGS2/MMP9 and the TNFα/AKT/GSK3/GLUT2 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with Theaflavins Targets PTGS2/MMP9 to Exert a Synergistic Hypoglycemic Effect  \nYuanyuan Wang †, Chenyin Qu†, Qiannan Di, Jingyi Zhang and Lixin Na *  \nAcademic Editor: Carmen Mannucci  \nReceived: 11 November 2025  \nRevised: 30 November 2025  \nAccepted: 24 December 2025  \nPublished: 27 December 2025  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \nThe College of Public Health, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Road, Pudong  \nNew Area, Shanghai 201318, China; [wangyy@sumhs.edu.cn](wangyy@sumhs.edu.cn) (Y.W.); [qcy1008@126.com](qcy1008@126.com) (C.Q.);  \n[diqn@sumhs.edu.cn](diqn@sumhs.edu.cn) (Q.D.); [zhangjy@sumhs.edu.cn](zhangjy@sumhs.edu.cn) (J.Z.)  \n* [Correspondence: nalx@sumhs.edu.cn](Correspondence: nalx@sumhs.edu.cn); Tel.: +86-13764255624 † These authors contributed equally to this work.  \nAbstract  \nBackground: This study aimed to explore the synergistic hypoglycemic effect and mechanism of 1-deoxynojirimycin (DNJ) in mulberry leaves and theaflavins (TFs) in black tea. Methods: The synergistic inhibition of α-glucosidase and α-amylase by DNJ-TFs was evaluated using enzyme assays and the Chou–Talalay model. Insulin-resistant (IR) HepG2 cells and high-fat diet (HFD)-induced type 2 diabetes mellitus mice were treated with DNJ, TFs, or DNJ-TFs, determining the efficacy of drug combinations by measuring glycolipidsand inflammatory factors. Network pharmacology and molecular docking were used to identify key target genes and signaling pathways, and CETSA experiments were used to verify the binding of drugs to targets. Key genes were further verified by immunofluorescence, Western blot, and Real-time PCR. Results: DNJ-TFs synergistically suppressed α-glucosidase (CI = 0.85) and α-amylase (CI = 0.76) . In HepG2 cells, DNJ-TFs ameliorated palmitic acid-induced IR by promoting glucose uptake, attenuating lipid accumulation, and regulating glycolipid metabolism. In HFD mice, DNJ-TFs counteracted hyperglycemia, dyslipidemia, systemic inflammation and oxidative stress, elevated HOMA-IR, and hepatic steatosis. Network pharmacology integrated with experimental validation identified PTGS2 and MMP9 as key binding targets of DNJ and TFs. Furthermore, DNJ-TFs could inhibit the increase in liver TNFα protein and the decrease in p-AKT, p-GSKα, p-GSKβ, and GLUT2 protein caused by high fat, both in vivo and in vitro. Conclusions: DNJ and TFs exert synergistic glucose-lowering effects by targeting PTGS2/MMP9 and regulating the TNFα/AKT/GSK3/GLUT2 axis, providing a promising natural therapeutic strategy for diabetes management.  \nKeywords: 1-deoxynojirimycin; theaflavins; type 2 diabetes mellitus (T2DM); synergistic  \n1. Introduction  \nAccording to the International Diabetes Federation (IDF) report in 2021, a total of 537 million people live with diabetes mellitus globally, and it is estimated that this number will rise to 643 million by 2030 and 783 million by 2045 [1] . As an important public health issue, patients with type 2 diabetes mellitus (T2DM) are usually accompanied by a range of severe complications, including diabetic foot conditions, retinopathy, nephropathy, neuropathy, and macrovascular diseases [2,3] . Currently, the treatment of T2DM mainly comprises using drugs, such as metformin, acarbose, and insulin injections [4] . However, long-term use of these drugs can lead to serious side effects [5] . In recent years, researchers  \nhave discovered that functional components in plants have great potential in preventing or alleviating chronic diseases [6] .  \nTraditional Chinese medicine theory believes that mulberry leaves are cold in nature, belong to the lung and liver meridians, and have the effect of dispersing wind-heat, thus clearing the lungs and moistening dryness. Black tea is warm in nature and can w","cbCaiepfpsFSylHA","https://ap.wps.com/l/cbCaiepfpsFSylHA","pdf",12168284,21,"English","# Abstract\n# Keywords\n# 1. Introduction\n## Background on type 2 diabetes and current treatments\n## Rationale for DNJ and theaflavins synergy\n## Role of network pharmacology and experimental validation\n# 2. Materials and Methods","[{\"question\":\"What is the main aim of combining DNJ and theaflavins in this study?\",\"answer\":\"To explore whether DNJ and TFs exert a synergistic hypoglycemic effect against type 2 diabetes and to clarify the mechanism involved.\"},{\"question\":\"How were the synergistic effects of DNJ-TFs evaluated?\",\"answer\":\"By measuring the combined inhibition of α-glucosidase and α-amylase using enzyme assays and the Chou–Talalay model.\"},{\"question\":\"Which targets and signaling axis are identified as key to the synergy?\",\"answer\":\"Network pharmacology and validation identify PTGS2 and MMP9 as key binding targets, and the effects are linked to regulation of the TNFα/AKT/GSK3/GLUT2 axis.\"}]","1-Deoxynojirimycin Combined with Theaflavins Targets PTGS2/MMP9 to Exert a Synergistic Hypoglycemic Effect | PDF",1790772235,53]