Current topics in medicinal chemistry最新文献

{"title":"Microtubule Stabilization as a Therapeutic Strategy: Updated Perspectives on Alzheimer's Disease and Neurodegenerative Tauopathies.","authors":"Darius J Yohannan, Kurt R Brunden, Thibault Alle","doi":"10.2174/0115680266465362260603045901","DOIUrl":"https://doi.org/10.2174/0115680266465362260603045901","url":null,"abstract":"","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148263832","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":"BMS-CTMC-2025-461Ubiquitin as a Putative Causal Immune Orchestrator in Initial COVID-19 Severity: A Mendelian Randomization and Multi-Omics Study.","authors":"Yueyue Wang, Sirui Cai, Yubo Sun, Junqi Zhang, Jiaqi Ding, Jing Wang, Xiyang Zhang, Yuanhang Chang, Zhenchi Fang, Anqi Yue, Kun Yang, Dongbo Jiang","doi":"10.2174/0115680266458416260529222552","DOIUrl":"https://doi.org/10.2174/0115680266458416260529222552","url":null,"abstract":"<p><strong>Introduction: </strong>The initial COVID-19 outbreak precipitated unprecedented health crises, with research impeded by containment protocols and the high mortality rate. While SARS-CoV-2 perturbs immune ubiquitin dynamics, the causal interplay between them remains uncharacterized.</p><p><strong>Methods: </strong>We integrated multi-omics and Mendelian randomization (MR) approaches, including bidirectional and two-step MR, to assess causality between ubiquitination and initial COVID-19 severity and to determine whether immune cells mediate this relationship. Transcriptomic profiling, protein-protein interaction networks, immune-correlation analysis, and an elastic-net-derived prognostic model were employed to explore these interactions further and identify potential biomarkers.</p><p><strong>Results: </strong>Bidirectional MR confirmed causal links between COVID-19 severity and ubiquitination, identifying 13 ubiquitin-related genes with altered expression. A two-step MR analysis of 731 immune cell traits revealed CD45RA+ CD8+ T cells as a mediator of severe COVID-19-induced ubiquitin dysregulation (mediation proportion: 5.797%). A prognostic model based on ISG15, UBE2B, and UBE2V1 demonstrated high predictive accuracy in the training cohort (AUC up to 0.977) and maintained good predictive power in the testing cohort (AUC: 0.672-0.819), with significant risk stratification (log-rank P < 0.001).</p><p><strong>Discussion: </strong>We propose that ubiquitin may function as a causal immune orchestrator, shaping clinical outcomes in the initial phase of COVID-19. The derived ubiquitin gene prognostic model demonstrates potential for clinical risk stratification, while pathway enrichment and druginteraction analyses suggest opportunities for repurposing ubiquitin-related targets in COVID-19 therapy.</p><p><strong>Conclusion: </strong>This ubiquitin-centric framework advances precision management of severe COVID- 19, highlights the potential of ubiquitin-related targets for drug development, and establishes a multi-omics MR-based paradigm for future viral pandemics.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257681","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":"Environmental Pollutant Tetrachloro-1,4-benzoquinone Exerts Neurotoxicity and Potential Protective Effects of Curcumin: A Network and Mendelian Randomization Analysis.","authors":"Chunshu Rong, Zhen Wei, Donge Xie, Qingyuan Wang, Haoxu Ren, Xu Wang, Dexi Zhao","doi":"10.2174/0115680266461615260518205032","DOIUrl":"https://doi.org/10.2174/0115680266461615260518205032","url":null,"abstract":"<p><strong>Introduction: </strong>The neurotoxicity mechanisms of tetrachloro-1,4-benzoquinone(TCBQ) remain poorly understood. This study integrated computational simulations validation to elucidate TCBQ-induced neurotoxicity.</p><p><strong>Methods: </strong>In our investigation of the neurotoxic effects of TCBQ, we employed a diverse range of analytical techniques, including protein-protein interaction (PPI) networks, screening for target genes and protective drugs, as well as performing KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) analyses. Additionally, we utilized advanced methodologies such as molecular docking and molecular dynamics simulations to gain deeper insights into the mechanisms underlying TCBQ's neurotoxicity. These comprehensive approaches enabled us to construct a detailed understanding of how TCBQ may contribute to neurotoxic outcomes. To further assess the potential connections between key target proteins and Alzheimer's disease, we utilized Mendelian randomization as a robust analytical strategy. This statistical method allowed us to explore the causal relationships that may exist between the identified proteins and the incidence of Alzheimer's disease, providing a clearer understanding of the biological pathways involved. For our analysis, we extracted summary-level data regarding the circulating levels of 4,907 proteins from a significant protein quantitative trait loci study conducted by the deCODE Genetics Consortium, which comprised a total of 35,559 individuals. Moreover, the outcome data for Alzheimer's disease were obtained from genome-wide association studies organized by the International Genomics of Alzheimer's Project (IGAP). This extensive research analyzed data from 17,008 participants who were diagnosed with Alzheimer's disease, alongside 37,154 control subjects, all of whom shared a European ancestry.</p><p><strong>Results: </strong>The results of integrated network analysis indicate that TCBQ may promote neurotoxicity through alzheimer 's disease. The main targets involved TNF, NOS2, IL6, and others. TCBQ and protective drug curcumin have a low binding score and compact complex with TNF, NOS2, IL6. 5 TNF subtype TNFSF13B, TNFRSF1B, TNFRSF13C, TNFSF12, NFRSF11B has a causal relationship with Alzheimer's disease.</p><p><strong>Discussion: </strong>TCBQ can promote neurotoxicity by increasing inflammation and alzheimer 's disease.</p><p><strong>Conclusion: </strong>Our study provides a theoretical basis for the subsequent experimental study of TCBQ in neurotoxicity. TNF plays an important role in alzheimer 's disease.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223937","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":"Effect of 3',4'-Dihydroxyflavonol on Striatum Antioxidant System in Focal Cerebral Ischemia-Reperfusion of Rat.","authors":"Murat Hosgor, Gozde Acar, Tugce Aladag, Ebru Kubra Uzdil, Rasim Mogulkoc, Abdulkerim Kasim Baltaci","doi":"10.2174/0115680266437734260523221414","DOIUrl":"https://doi.org/10.2174/0115680266437734260523221414","url":null,"abstract":"<p><strong>Introduction: </strong>The present study aimed to determine the effect of 1-week 3'-,4'- Dihydroxyflavonol (DiOHF) supplementation on the antioxidant system in the striatum tissue after brain ischemia-reperfusion in rats. In our current study, the relationship between DiOHF and the antioxidant systems GPx, SOD, CAT, and Trx2 was investigated for the first time in the striatum tissue of rats undergoing focal brain ischemia-reperfusion.</p><p><strong>Methods: </strong>A total of 28 Wistar-albino male rats were used, and the groups were as follows.</p><p><strong>Control: </strong>No anaesthesia or surgical procedure was performed on the animals in this group. Sham: After general anaesthesia was induced in the animals in this group, the carotid artery regions were opened and closed. After the application, the vehicle was supplemented for 1 week. Ischemia- Reperfusion (I/R): After the carotid arteries were isolated in the rats under general anaesthesia, they were ligated for 30 minutes, and ischemia was induced, followed by reperfusion. I/R + DiOHF Supplemented: DiOHF was supplemented after the I/R for 1 week.</p><p><strong>Results: </strong>Results of the study indicate that one week of I/R suppressed antioxidant markers such as GPx, SOD, CAT, and Trx2 in the striatum of rats. However, one week post-ischemic reperfusion treatment with DiOHF ameliorated these changes in the striatum.</p><p><strong>Discussion: </strong>The oxidant/antioxidant balance in the striatum tissue was disrupted with I/R. DiOHF supplementation, together with I/R, corrected the changes that occurred due to I/R. This study has certain limitations that should be taken into account. In future studies, significant progress can be made in determining the effectiveness of treatment in brain ischemia-reperfusion, which can cause significant health problems, by performing the analyses at different time intervals with different experimental models and different durations.</p><p><strong>Conclusion: </strong>DiOHF administration for one week after experimental cerebral ischemia-reperfusion in rats exerts beneficial effects on the antioxidant system in striatum tissue.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223898","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":"A Review on Varied Mechanistic Pathways of Four Major Isothiocyanates in Cancer Suppression and Their Synergistic Action in Cancer Therapy.","authors":"Beware Dkhar, Partha Pratim Gogoi, Basanta Sinha, Penlisola Longkumer, Nichan Boruah, Mhasilhoutuo Pucho, Ilavanalangki Lytan, Upasana Bora Sinha","doi":"10.2174/0115680266394550251205071956","DOIUrl":"https://doi.org/10.2174/0115680266394550251205071956","url":null,"abstract":"<p><p>This review explores the anticancer potential of key isothiocyanates (ITCs), including phenyl, allyl, and benzyl isothiocyanates (BITCs), and sulforaphane, with a focus on their synergistic effects with conventional cancer therapies. Derived primarily from Brassica vegetables, these compounds modulate apoptosis, redox balance, and epigenetic regulation, contributing to their chemopreventive properties. Emerging evidence suggests that ITCs can enhance chemotherapy and radiotherapy by sensitizing cancer cells and overcoming resistance; however, their full therapeutic potential remains underexplored, necessitating further research. ITCs exert anticancer effects through multiple mechanisms, including the activation of detoxification enzymes, suppression of oncogenic pathways, induction of apoptosis, and regulation of oxidative stress. Key signaling pathways, such as Nrf2, NF-κB, and MAPK, play critical roles in inhibiting tumor growth, metastasis, and angiogenesis. Additionally, ITCs can enhance conventional therapies by increasing cancer cell sensitivity and reducing adverse effects, positioning them as promising adjunctive agents in cancer treatment. The synergy between ITCs and conventional therapies holds significant potential for improving treatment outcomes. Nevertheless, optimizing their clinical application requires further investigation into appropriate dosing, delivery methods, and combination strategies. A deeper understanding of their molecular mechanisms and synergistic interactions will facilitate their integration into cancer therapies, ultimately enhancing therapeutic efficacy and patient outcomes.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204169","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":"Interlinked Microbiota-Metabolite-Epigenome Dynamics in the Gut-Heart-Ovary Axis: New Perspectives on Cardiometabolic Risk in Polycystic Ovary Syndrome.","authors":"Harshal D Pawar, Nikhil Mahajan, Yogeeta O Agrawal, Sameer N Goyal","doi":"10.2174/0115680266447242260512114609","DOIUrl":"https://doi.org/10.2174/0115680266447242260512114609","url":null,"abstract":"<p><p>Beyond reproductive dysfunction, polycystic ovarian syndrome (PCOS) is a complex endocrine condition that significantly raises metabolic and cardiovascular morbidity in PCOSaffected individuals. There is growing evidence that the gut microbiota plays a vital role in the pathogenesis of PCOS and the cardiometabolic problems associated with it. This review examined the novel premise of the gut-heart-ovary axis, emphasising how gut microbial dysbiosis in PCOS interferes with critical processes related to inflammation, insulin resistance, lipid metabolism, and endothelial function, ultimately leading to problems with the heart. It has been demonstrated that changes in microbial-derived metabolites, such as bile acids, trimethylamine-N-oxide (TMAO), and short-chain fatty acids (SCFAs), damage the intestinal barrier, cause systemic inflammation, and worsen vascular dysfunction, thereby aggravating mechanisms underlying the development of cardiovascular disease. Additionally, a recent study indicates that gut dysbiosis and cardiovascular disease in PCOS may be mechanistically linked through microbiota-microRNA interactions and epigenetic changes brought on by gut-derived signals. This study emphasises the need for comprehensive approaches to decipher the intricate interactions underlying PCOS and its cardiometabolic aftereffects by clarifying the triangle crosstalk among the gut, heart, and ovary. Additionally, it finds new genetic targets for therapeutic intervention with implications for cardiovascular and reproductive health, especially in the field of microbiota-centered targeted therapy.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204425","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":"Deciphering the PI3K-AKT-mTOR Signalling Pathway in Cancer: A Mechanistic Insight.","authors":"Chetana C Galav, Somali Sanyal, Sukriti Singh, Manish Dwivedi","doi":"10.2174/0115680266429226260509044436","DOIUrl":"https://doi.org/10.2174/0115680266429226260509044436","url":null,"abstract":"<p><p>The PI3K-AKT-mTOR signalling pathway plays a central role in regulating cell growth, survival, and proliferation, significantly influencing the development and progression of cancer. This review examines the mechanistic and structural complexities of the major components of the PI3K-AKT-mTOR pathway, exploring their potential as therapeutic targets in cancer. Aberrant activation of this signalling pathway has been strongly linked to the initiation and progression of various cancers, including breast, ovarian, gastric, lung, prostate, endometrial, laryngeal, and hepatocellular carcinoma, among others. The review highlights current therapeutic strategies that aim to inhibit PI3K, AKT, and mTOR in cancer treatment, emphasising the use of small-molecule inhibitors and monoclonal antibodies. Additionally, it discusses the promise of combination therapies in enhancing treatment effectiveness and addressing resistance mechanisms that may arise during pathway inhibition. Understanding these resistance mechanisms and developing novel strategies to overcome them are critical for improving therapeutic outcomes for cancer patients. Overall, this study provides a thorough examination of the PI3K-AKT-mTOR pathway, its potential for therapeutic intervention, and the evolving trends in cancer treatment, offering valuable insights for both researchers and clinicians.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204333","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":"AI-Powered Traditional Medicine Discovery: A Structured Narrative Review of \"AI\"-Titled Studies.","authors":"Chen Shaodong, Muhammad Shahzad Aslam, Liang Huiqing","doi":"10.2174/0115680266470947260514050449","DOIUrl":"https://doi.org/10.2174/0115680266470947260514050449","url":null,"abstract":"<p><strong>Introduction: </strong>Artificial intelligence is increasingly applied in Traditional Medicine research, yet whether studies explicitly self-labelled as \"AI-based\" substantively advance drug-discovery remains unclear. This review characterises how studies with \"AI\" in the article title apply artificial intelligence to Traditional Medicine drug-discovery and identifies methodological patterns, limitations, and emerging directions.</p><p><strong>Methods: </strong>Five databases were searched for records containing artificial intelligence terminology in the title, retrieving over 2,000 records. After staged deduplication and structured screening against predefined criteria, twelve primary studies were included. Data were extracted across Traditional Medicine systems, computational techniques, discovery tasks, data sources, and validation strategies, and synthesised narratively due to heterogeneity.</p><p><strong>Results: </strong>The included studies covered single herbs, classical multi-herb formulas, Traditional Medicine compound libraries, and safety-oriented modelling. Artificial intelligence methods ranged from supervised learning and deep learning to optimisation routines, molecular modelling, and network-based approaches. Most studies combined computational prediction with cell-based or animal-based validation, while only one linked algorithmic outputs to a clinical trial. Convergent biological signals were noted across metabolic, inflammatory, and endothelial pathways, and model performance frequently exceeded baseline statistical approaches.</p><p><strong>Discussion: </strong>The included studies demonstrated stronger experimental grounding than most external AI-Traditional Medicine work, yet predictive sophistication consistently outpaced clinical validation. Inconsistent reporting standards and variable use of the term \"AI\" limit cross-study comparability and generalisability.</p><p><strong>Conclusion: </strong>AI-titled Traditional Medicine studies form a small but methodologically diverse evidence subset demonstrating repeated predictive success and moderate experimental support, yet rarely achieving clinical validation. Future progress requires clearer reporting, stronger external testing, and integrated pathways connecting computational outputs to reproducible biological and clinical evidence.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204310","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":"Neuroprotective Phytochemicals Targeting Amyloid and Tau Pathologies.","authors":"Irfan Ahmed, Yaasir Ahmed Ansari, Gazala Parveen, Kavita Shukla, Manish Bhise, Satnam Singh, Uzma Praveen Shaikh, Rafi Ahmed, Israr Ansari, Ajay Kumar","doi":"10.2174/0115680266446356260226085409","DOIUrl":"https://doi.org/10.2174/0115680266446356260226085409","url":null,"abstract":"<p><p>The prevalence of Alzheimer's disease stands at more than 55 million individuals in the world, with estimates showing that the figure will increase to 152 million in 2050. Existing treatment methods are mostly symptomatic and do not address the underlying molecular disruptions, such as oxidative stress, mitochondrial dysfunction, and neuroinflammation. Neurodegeneration mediated by convergent pathways of these processes occurs through Aβ and hyperphosphorylated Tau. This is an overall review summarizing evidence from the PubMed, Scopus, and Web of Science databases as of 2025 on phytochemicals that can address both amyloid and tau pathologies simultaneously. This study presents a comprehensive assessment of more than 100 bioactive compounds across 7 chemical families with dual anti-amyloid and anti-tau effects, without prior reviews that address separate pathological targets or isolated classes of compounds with bioactivity. Major phytochemicals, such as curcumin, resveratrol, and epigallocatechin-3- gallate, suppress the activity of the beta-secretase, prevent the formation of amyloid fibrils, inhibit glycogen synthase kinase-3beta-mediated tau phosphorylation, and promote autophagy-lysosomal clearance. These molecules regulate NF-erythroid-2-related factor 2 signaling to inhibit reactive oxygen species and inhibit NF-κB-mediated neuroinflammation. Preclinical models show reductions in cognitive and neuropathological burden, but bioavailability and blood-brain barrier penetration pose barriers to clinical translation. Developed nanotechnology-based systems of delivery and structural modifications have potential in overcoming pharmacokinetic constraints. This represents a multi-target candidate therapy, a paradigm shift from the single-pathway therapeutics of the past, which may provide disease-modifying strategies beyond symptom management of Alzheimer's disease.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148136976","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":"D-Dopachrome Tautomerase Regulates Synovial Fibrosis and Macrophage Polarization via NF-κB/CCL2 Signaling Pathway in Knee Osteoarthritis.","authors":"Jibing Wang, Pengfei Guo, Xing Jin, Zhaoxiang Meng, Bo Chen","doi":"10.2174/0115680266484865260522102846","DOIUrl":"https://doi.org/10.2174/0115680266484865260522102846","url":null,"abstract":"<p><strong>Introduction: </strong>This study aimed to investigate the regulatory function of D-dopachrome tautomerase (DDT) in the occurrence and development of Knee Osteoarthritis (KOA).</p><p><strong>Methods: </strong>Single-cell data (GSE248453) and transcriptome data (GSE283079) related to KOA were retrieved from the GEO database. Seurat, limma, and clusterProfiler packages were used for computational analyses. For in vitro experiments, mouse Synovial Fibroblasts (SFs) were transfected with si-DDT and then stimulated with Lipopolysaccharide (LPS). RAW264.7 cells were cultured with SFs-conditioned medium to assess macrophage polarization. Finally, Transwell, qRT-PCR, Western blot, and NF-κB agonist rescue assays were performed for validation.</p><p><strong>Results: </strong>Computational analysis showed that DDT and chemokine-ligand-2 (CCL2) were primarily expressed in fibroblasts and macrophages in KOA and showed a positive correlation with each other. DDT was upregulated in LPS-induced SFs, while its knockdown inhibited the migration of SFs and the expressions of fibrosis-related genes, NF-κB pathway, and CCL2. However, these effects were reversed by the NF-κB agonist. DDT silencing suppressed the levels of M1 markers (IL-6, IL-1β) and elevated those of M2 markers (IL-4, CD206) in macrophages.</p><p><strong>Discussion: </strong>DDT acted as a key regulator in KOA pathogenesis. It was observed that knockdown of DDT downregulated the expressions of genes related to fibrosis and tissue remodeling (including TGF‑β, COL1A1, and TIMP1), suppressed M1 macrophage polarization, and promoted M2 phenotype, potentially through modulation of the NF‑κB/CCL2 pathway.</p><p><strong>Conclusion: </strong>This study identified DDT as a potential therapeutic target for the clinical treatment of KOA, providing new insights into the pathogenic mechanism of the disease.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148136940","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}