Chemical Biology & Drug Design最新文献

{"title":"Investigation of the Inhibitory Effects and Underlying Mechanisms of Vitexin Derivatives Targeting CDK1 in HCT Colorectal Cancer Cells","authors":"Ying Zhao,&nbsp;Dan Hua,&nbsp;Chenying Zhao,&nbsp;Hailong Shi,&nbsp;Chaojun Han,&nbsp;Xingmei Zhu,&nbsp;Chuan Wang,&nbsp;Bin Wang,&nbsp;Jiping Liu,&nbsp;Yongheng Shi","doi":"10.1111/cbdd.70292","DOIUrl":"10.1111/cbdd.70292","url":null,"abstract":"<div>\u0000 \u0000 <p>This study designs and synthesizes a series of vitexin derivatives to evaluate their inhibitory activity against human colon cancer HCT-116 cells and to explore the underlying mechanisms. Antiproliferative effects are assessed using the CCK-8 assay. Molecular docking with Schrödinger software and molecular dynamics simulations analyze interactions between candidate compounds and CDK1. Cell cycle distribution is determined by flow cytometry, while western blotting, immunofluorescence, and CDK inhibition assays evaluate CDK1/cyclin B expression. Most derivatives show stronger inhibitory activity than the parent compound. Vitexin exhibits an IC₅₀ of 210.23 ± 40.89 μM, whereas Butylated vitexin (M3) displays markedly enhanced potency (IC₅₀ = 8.73 ± 1.40 μM) and induces G₂/M phase arrest. Molecular docking reveals strong binding affinity between M3 and CDK1 (Docking score −10.127), and molecular dynamics simulations confirm the stability of the M3-CDK1 complex with inhibitory effects comparable to flavopiridol (FP). Furthermore, M3 downregulates CDK1/cyclin B expression in HCT-116 cells (IC₅₀ = 9.83 ± 2.65 μM). M3 may suppress HCT-116 cell proliferation by targeting CDK1/cyclin B and inducing G₂/M phase arrest.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147629441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, Bioactivity and Molecular Modeling Studies on Benzimidazole Derivatives and Its Isosteres as Potent AChE/BChE and GSK3β Inhibitors for Alzheimer's Disease","authors":"Gözde Sayar,&nbsp;Sulunay Parlar,&nbsp;Ayse Hande Tarikogullari,&nbsp;Mumin Alper Erdoğan,&nbsp;Guliz Armagan,&nbsp;Vildan Alptuzun","doi":"10.1111/cbdd.70285","DOIUrl":"10.1111/cbdd.70285","url":null,"abstract":"<p>A series of benzimidazoles and its analogs (benzoxazoles and benzothiazoles) bearing a benzohydrazide-hydrazones moiety at the 2-position were designed and synthesized as potential acetylcholinesterase (AChE) inhibitors. Cholinesterase (ChE) inhibitory activity results showed that all compounds displayed good inhibition of AChE, whereas only some of the compounds were active against BChE. Among the title compounds, it was found that all benzimidazole series were selective towards AChE. Kinetic analysis and molecular modeling studies were conducted on the most active compounds, namely <b>1j</b> for AChE and <b>3g</b> for BChE inhibition. The kinetic results showed that the tested compounds exhibited a mixed-type inhibition mechanism on both enzymes. In cell culture studies, all compounds were evaluated for their neuroprotective effects against hydrogen peroxide (H₂O₂)-induced oxidative stress in the SH-SY5Y human neuroblastoma cell line. Several compounds demonstrated more than 30% neuroprotection at a low concentration (1 μM) in the presence of H₂O₂. Selected compounds, chosen based on their EC₅₀ values, were further examined for their effects on glycogen synthase kinase-3 beta (GSK3β), an enzyme whose activity has been reported to be increased in the brains of patients with Alzheimer's disease (AD). The inhibition of GSK3β was assessed by measuring phosphorylated GSK3β (pGSK3β, Ser9) protein expression via Western Blot analysis under oxidative stress conditions. Among the tested compounds, <b>1l</b>, <b>2b</b>, <b>2j</b>, and <b>3l</b> significantly increased pGSK3β (Ser9) protein levels compared to cells treated with tideglusib, a known GSK3β inhibitor.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13052373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147624865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the Menin–KMT2A Interface: Medicinal Chemistry Rules Governing Reversible, Covalent, and Degrader Inhibitors","authors":"Ahmed A. Al-Karmalawy,&nbsp;Mohamed E. Eissa,&nbsp;Tarek A. Yousef,&nbsp;Marwa Sharaky,&nbsp;Arwa Omar Al Khatib,&nbsp;Samia S. Hawas","doi":"10.1111/cbdd.70291","DOIUrl":"10.1111/cbdd.70291","url":null,"abstract":"<div>\u0000 \u0000 <p>The menin–lysine methyltransferase 2A acute leukemia (KMT2A) protein–protein interaction has emerged as a clinically validated epigenetic target in acute leukemia, following the approval of the reversible menin inhibitor Revumenib for <i>KMT2A</i>-rearranged and nucleophosmin 1 (NPM1)-mutant disease. This success transformed a once “undruggable” interface into a tractable binding pocket, triggering the rapid expansion of medicinal-chemistry strategies aimed at achieving deeper and more durable transcriptional reprogramming. This review analyzes the full menin-inhibitor landscape from a medicinal-chemistry perspective, integrating reversible, covalent, and degrader-oriented modalities within a unified structure–activity framework. We highlight how scaffold architecture, pocket occupancy, electrophile placement toward Cys329, and polarity tuning control binding mode, residence time, metabolic stability, resistance susceptibility, and pharmacodynamic durability. Across all chemical classes, sustained target engagement—rather than equilibrium affinity alone—emerges as the dominant determinant of antileukemic efficacy. By integrating structure–activity relationship (SAR), resistance mechanisms, safety considerations, and translational scope across oncology and metabolic indications, this review provides a roadmap for the rational design of next-generation menin inhibitors and establishes menin as a model system for modern epigenetic drug discovery.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147619125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An AI-Guided Structure-Based Strategy for the Discovery and Biological Validation of Natural Products Targeting the Vitamin D Receptor From YSQYP in Diabetic Kidney Disease","authors":"Xinze Liu,&nbsp;Jingxuan Shi,&nbsp;Jiaqi An,&nbsp;Qiaoya He,&nbsp;Yuanyuan Jiao,&nbsp;Yue Yang,&nbsp;Hui Shi,&nbsp;Hao Zeng,&nbsp;Sixuan Wang,&nbsp;Li Zhuo,&nbsp;Wenge Li","doi":"10.1111/cbdd.70289","DOIUrl":"10.1111/cbdd.70289","url":null,"abstract":"<div>\u0000 \u0000 <p>Diabetic kidney disease (DKD) is among the most common and severe complications of diabetes mellitus, with current treatments providing limited efficacy. Yi-Shen-Qu-Yu prescription (YSQYP), a traditional Chinese herbal formula, has demonstrated clinical efficacy in the treatment of DKD; however, its bioactive constituents and underlying mechanisms remain poorly defined. This study proposes a structure-based and deep learning–guided screening strategy to identify active compounds within YSQYP that target the vitamin D receptor (VDR). An integrated screening strategy was established, combining virtual screening using conventional docking methods and deep learning tools (CarsiDock and RTMScore), as well as biophysical validation through surface plasmon resonance (SPR). Subsequently, the protective effects of candidate compounds against high-glucose-induced podocyte injury were further validated using biological assays. Among the screened constituents, isorhamnetin, hederagenin, and (+)-catechin exhibited the strongest binding affinities for VDR. Functional assays confirmed their capacity to mitigate high-glucose-induced cytotoxicity and apoptosis in podocytes, with isorhamnetin showing the most potent protective effect. Collectively, this study establishes an efficient strategy for natural product screening and identifies promising VDR-targeting compounds from YSQYP, providing novel therapeutic candidates for the treatment of DKD.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Schiff Base Derivative Triazines: Their Synthesis, Molecular Docking Studies, and Anticancer Activities in Human Lung Cancer Cells","authors":"Elif Şenkuytu,&nbsp;Seda Mesci,&nbsp;Deryanur Kılıç,&nbsp;Burak Yazgan,&nbsp;Tuğba Taş Özdemir,&nbsp;Tuba Yıldırım","doi":"10.1111/cbdd.70278","DOIUrl":"10.1111/cbdd.70278","url":null,"abstract":"<div>\u0000 \u0000 <p>Lung cancer has high mortality rates among both men and women worldwide. Nevertheless, mortality rates have been reported to decline with the advancement of novel therapeutic agents and the identification of new molecular targets. Schiff bases and triazine compounds have significant biological activity. For this purpose, new Schiff base derivative triazine compounds (<b>TrzSchf 1–3</b>) were synthesized in our study. The activities of the new compounds, characterized by spectroscopic techniques, against A549 lung cancer and MRC5 normal lung cells were identified in a series of studies. It was observed that <b>TrzSchf 1–3</b> generally showed a growth-inhibitory effect against lung cancer cells (A549) and a non-toxic effect against normal lung cells (MRC5). Notably, <b>TrzSchf 1</b> and <b>TrzSchf 2, 3</b> exhibited prominent cytotoxic effects in A549 cells, with IC₅₀ values of 14.24 and &gt; 50 μM, respectively. It was observed that the compound with the most potent cytotoxicity against lung cancer cells was <b>TrzSchf 1</b> (Selective Index: 3.62). In A549 cells, an increase in MAPK gene expression was observed for all compounds. It was observed that the expression of Caspase-3, CD40, CHK1, P27, P38, and P53 proapoptotic proteins increased by all compounds (<b>TrzSchf 1–3</b>), whereas the expression of antiapoptotic proteins such as BCL-2 and NFκB decreased by these compounds. The compounds are thought to be potential inhibitors of BCL-2 and NFκB, which are associated with cell death. Complementary and guiding <i>in silico</i> studies supported the experimental findings. BCL-2 was determined as the most favorable molecular target based on docking scores, and e-pharmacophore modeling further revealed key interaction features and enabled SAR analysis. The drug-likeness potential of the <b>TrzSchf</b> derivatives was evaluated based on Lipinski's Rule of Five parameters. Overall, both experimental and computational results suggest that <b>TrzSchf 1–3</b> are promising lead candidates for further investigation in lung cancer therapy.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147577035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-Omics and Machine Learning-Driven Discovery of ABCC8 (SUR1) for Diabetes Mellitus: Integrating Molecular Insights on Nigella sativa Bioactives and Sulfonylurea","authors":"Mohd Adnan,&nbsp;Arif Jamal Siddiqui,&nbsp;Insaf Bahrini,&nbsp;Md Imtaiyaz Hassan,&nbsp;Riadh Badraoui,&nbsp;Mitesh Patel","doi":"10.1111/cbdd.70277","DOIUrl":"10.1111/cbdd.70277","url":null,"abstract":"<div>\u0000 \u0000 <p>Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia and pancreatic β-cell dysfunction. The ATP-sensitive potassium KATP channel, regulated by ATP-binding cassette subfamily C member 8 (ABCC8/SUR1), plays a pivotal role in insulin secretion, and its dysregulation is associated with neonatal and type 2 diabetes. In this study, we employed an integrated computational framework to explore the structural, regulatory, and ligand-interaction landscape of ABCC8. Transcriptomic analysis of publicly available datasets (GSE41762, GSE25724) indicated significant upregulation of ABCC8 in diabetic samples (<i>q</i>-values: 0.09597 and 0.04781), suggesting a potential compensatory response to hyperglycemia. Structural analyses identified conserved ATP-binding motifs and a predicted disordered region (residues 621–676), which may influence channel gating and interaction dynamics. In silico virtual screening of FDA-approved sulfonylureas and <i>Nigella sativa</i> derived bioactive compounds revealed favorable predicted binding affinities toward ABCC8. Selected <i>N. sativa</i> compounds exhibited docking scores ranging from −4.1 to −9.7 kcal/mol, comparable to those of sulfonylureas (−8.2 to −3.6 kcal/mol). Molecular dynamics simulations further suggested stable protein–ligand complexes based on RMSD, radius of gyration, and solvent-accessible surface area profiles. Pathway enrichment and predictive miRNA analyses implicated ABCC8 in insulin secretion, K ATPchannel regulation, and metabolic signaling pathways, with miR-375 and miR-29 predicted to be involved in ABCC8 regulation. Overall, this study provides computational and predictive insights into ABCC8 structure, regulation, and ligand interactions, highlighting candidate molecules for further investigation. Experimental validation is required to confirm these findings and to evaluate their translational relevance for diabetes management.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147535075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Silver(I) and Gold(I) N-Heterocyclic Carbene Complexes Induce ROS-Dependent Autophagic Cell Death in Human Hepatoma Cell Line HepG2","authors":"Rocchina Miglionico,&nbsp;Francesco Viceconte,&nbsp;Maria Francesca Armentano,&nbsp;Annaluisa Mariconda,&nbsp;Ilaria Nigro,&nbsp;Pasquale Longo,&nbsp;Faustino Bisaccia","doi":"10.1111/cbdd.70283","DOIUrl":"10.1111/cbdd.70283","url":null,"abstract":"<p>Hepatocellular carcinoma is one of the most aggressive malignancies worldwide, with limited treatment options and high resistance to conventional therapies. Developing novel therapeutic strategies that target alternative cell death mechanisms is crucial for overcoming treatment resistance. This study evaluated the cytotoxicity of eight sulfonated silver(I) and gold(I) N-heterocyclic carbene (NHC) complexes—four newly synthesized—against human liver cancer cells and investigated the mechanisms of the compounds that exhibited higher selectivity for cancer cells compared to non-malignant liver cells. Morphological analysis revealed distinct features of autophagy rather than apoptosis, as confirmed by the absence of chromatin condensation, caspase-3 activation, and PARP-1 cleavage. Instead, both complexes strongly upregulated Beclin-1 and LC3-II expression—key autophagy markers—while inhibiting the AKT/mTOR signaling pathway. The observed cytotoxic effects were associated with a significant increase in reactive oxygen species (ROS) production. Pre-treatment with the antioxidant N-acetyl-L-cysteine completely abolished both cytotoxicity and autophagy induction. These findings demonstrate that silver(I) and gold(I) NHC complexes induce ROS-dependent autophagic cell death in this kind of cancer cells. The ability of these compounds to trigger non-apoptotic cell death mechanisms highlights their potential as promising candidates for overcoming apoptosis resistance in HCC therapy, warranting further in vivo investigations.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13031429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147535240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thiadiazole-Derived VEGFR-2 Inhibitors: From Design to Anticancer Evaluation","authors":"Aisha A. Alsfouk,&nbsp;Eslam B. Elkaeed,&nbsp;Hazem Elkady,&nbsp;Walid E. Elgammal,&nbsp;Hazem A. Mahdy,&nbsp;Ahmed Nofal,&nbsp;Ibrahim H. Eissa,&nbsp;Dalal Z. Husein,&nbsp;Ibrahim M. Ibrahim,&nbsp;Mahmoud S. Elkotamy,&nbsp;Ahmed M. Metwaly","doi":"10.1111/cbdd.70280","DOIUrl":"10.1111/cbdd.70280","url":null,"abstract":"<div>\u0000 \u0000 <p>In this study, a series of novel thiadiazole derivatives (<b>7a</b>, <b>7b</b>, <b>9a</b>, <b>9b</b>, and <b>9c</b>) were rationally designed as potential VEGFR-2 inhibitors using a pharmacophore-guided strategy. The compounds were synthesized and assessed for their antiangiogenic and anticancer effects. Among them, compound <b>9b</b> showed the strongest VEGFR-2 inhibition (IC₅₀ = 0.030 ± 0.001 μM), outperforming the reference drug Sorafenib. Cytotoxicity tests revealed that <b>9b</b> was highly effective against MCF-7 breast cancer cells (IC₅₀ = 8.06 ± 0.7 μM) while exhibiting minimal toxicity toward normal WI-38 cells. Flow cytometry demonstrated that <b>9b</b> induced significant G2/M cell cycle arrest and increased apoptosis, supported by molecular data showing upregulation of caspase-3 and Bax and downregulation of Bcl-2, indicating activation of the intrinsic apoptotic pathway. Extensive in silico studies—including molecular docking, 200 ns molecular dynamics simulations, interaction mapping, principal component analysis of trajectories, and free energy landscape analysis—confirmed that <b>9b</b> binds stably and efficiently within the VEGFR-2 active site. Overall, these results highlight compound <b>9b</b> as a promising VEGFR-2-targeted antiangiogenic agent with potent enzymatic and cellular activity, favorable selectivity, and mechanistic validation through combined experimental and computational approaches.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147517555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Throughput Platform for Discovery of Chemical Inhibitors of Heat Shock Protein 70 (Hsp70): Adaptation for the Specialized Bacterial HscA–HscB–IscU Complex","authors":"Arielle Shkedi,&nbsp;Aneta Grabinska-Rogala,&nbsp;Jason Hernandez,&nbsp;Rafał Dutkiewicz,&nbsp;Jaroslaw Marszalek,&nbsp;Jason E. Gestwicki","doi":"10.1111/cbdd.70281","DOIUrl":"10.1111/cbdd.70281","url":null,"abstract":"<div>\u0000 \u0000 <p>Adenosine triphosphatases (ATPases) power essential cellular processes, but they commonly achieve full activity only within multi-protein assemblies, where cofactors and partner proteins tune their function. Yet, most high-throughput screening (HTS) campaigns that target ATPases tend to use highly purified enzymes without these important partners. Here we present a high-throughput platform for discovering small-molecule modulators of the bacterial heat shock protein (Hsp70) system: HscA–HscB–IscU, a promising anti-bacterial target. In this multi-protein complex, HscA has ATPase activity that is stimulated by HscB and IscU, such that inhibitors might act at either the enzyme active site or at protein–protein interactions (PPIs). To enable discovery of such molecules, we reconstituted purified HscA, HscB, and IscU, optimized their ratios to favor the active complex and then miniaturized a quinaldine red-based, phosphate detection assay to 384-well plates (Z′ = 0.68). A pilot screen of ~2000 bioactive compounds identified 253 primary hits, suggesting an abnormally high hit rate (13.6%); however, many of these signals were attributable to compound insolubility and could be triaged using aggregation-detection strategies. Collectively, this workflow establishes a scalable platform for discovering chemical probes of the HscA-HscB-IscU system. More broadly, this work provides the foundation for HTS campaigns targeting reconstituted, multi-protein complexes containing ATPase activity.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147517468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tetrahydropalmatine Alleviates Osteoarthritis-Associated Pain and Inflammation by Suppressing KDM4A/MDM2/HIF-1α-Mediated M1 Macrophage Polarization","authors":"Xiaobo Chen,&nbsp;Xiaoyong Sun,&nbsp;Qiuming Zhong,&nbsp;Hongxia Gan,&nbsp;Weiping Lv,&nbsp;Ying Yang","doi":"10.1111/cbdd.70279","DOIUrl":"10.1111/cbdd.70279","url":null,"abstract":"<div>\u0000 \u0000 <p>Osteoarthritis (OA)-associated pain, driven by M1 macrophage polarization and inflammation, lacks effective therapies. Tetrahydropalmatine (THP), known for its anti-inflammatory and analgesic properties, was evaluated for its effects on OA-induced pain and macrophage polarization. A destabilization of the medial meniscus (DMM)-induced OA mouse model and lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages were used. Behavioral tests, histology, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting (WB), and immunohistochemistry (IHC) were used to assess pain, inflammation, and the expression of lysine demethylase 4A (KDM4A), murine double minute 2 (MDM2), and hypoxia-inducible factor-1α (HIF-1α). THP treatment alleviated OA-induced pain and cartilage damage and reduced CD86 expression, and reduced the expression of pro-inflammatory factors tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and key signaling molecules (KDM4A, MDM2, and HIF-1α). Mechanistically, KDM4A directly bound to the MDM2 promoter and activated its transcription via H3K9me3 demethylation, whereas MDM2 enhanced HIF-1α signaling to promote M1 polarization. Overexpression of KDM4A reversed the inhibitory effects of THP on MDM2/HIF-1α signaling and inflammation. These findings indicate that THP mitigates OA-associated pain and inflammation by blocking KDM4A-mediated MDM2 transcription and suppressing HIF-1α-dependent M1 macrophage polarization, highlighting the KDM4A-MDM2-HIF-1α axis as a potential therapeutic target.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147488726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}