Chemical Biology & Drug Design最新文献

{"title":"Integrating Chemistry and Biology: Evolving Design Principles Across Therapeutic Modalities","authors":"Satoshi Uchida, Hiroaki Sawamoto","doi":"10.1111/cbdd.70388","DOIUrl":"https://doi.org/10.1111/cbdd.70388","url":null,"abstract":"","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823263","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":"Identification of Hub Gene Characteristics and Immune Landscapes Across Aging Subtypes in Atherosclerosis: A Machine Learning-Based Multi-Omics Study With Experimental Verification","authors":"Qiyu Fan,&nbsp;Kang Chen,&nbsp;Jibin Liu,&nbsp;Xun Diao,&nbsp;Zhuopeng Xia,&nbsp;Haizhong Yu,&nbsp;Haixia Zhu","doi":"10.1111/cbdd.70382","DOIUrl":"10.1111/cbdd.70382","url":null,"abstract":"<p>Aging is a major risk factor for atherosclerosis (AS), but the aging-associated molecular characteristics and immune heterogeneity of AS remain incompletely understood. This study aimed to identify aging-related hub genes and characterize immune landscapes across aging subtypes of AS using integrated bioinformatics and experimental validation. AS-related candidate genes were found by overlapping DEGs identified by limma and key module genes identified by Weighted Correlation Network Analysis (WGCNA) based on the GSE100927 dataset. Consensus clustering based on aging-related DEGs (differential expression analysis based on 125 aging-related genes between AS and control) was performed to identify aging subtypes and characterize immune landscapes. Typical genes were picked out using four machine learning models: Support Vector Machine (SVM), Random Forest (RF), eXtreme Gradient Boosting (XGB), and Generalized Linear Model (GLM). The expression of central genes was verified through single—cell data analysis. Patients with AS were enrolled (<i>n</i> = 30), and atherosclerotic plaque and adjacent normal arterial tissues were collected. Quantitative Polymerase Chain Reaction (qPCR) validation was performed in atherosclerotic plaques and oxidized Low-Density Lipoprotein (ox-LDL)-treated THP-1 macrophage. The effect of crucial genes on ox-LDL-induced THP-1 macrophage inflammatory response and foaming were validated by qPCR, ELISA and Oil Red O Staining. We identified 76 aging-related DEGs and classified AS samples into two aging-related subtypes (C1 and C2) with distinct immune infiltration characteristics. Machine learning analysis based on 43 candidate genes identified 5 hub genes: heat shock protein family B (small) member 7 (HSPB7), myelin expression factor 2 (MYEF2), dual specificity phosphatase 26 (DUSP26), tandem C2 domains, nuclear (TC2N), and phospholamban (PLN), whose expression patterns were further validated by single-cell RNA sequencing. Moreover, TC2N and PLN were significantly downregulated in atherosclerotic plaque tissues. TC2N and PLN expressions in atherosclerotic plaque tissue of AS patient were significantly reduced. TC2N was significantly decreased in ox-LDL-treated THP-1 macrophage. TC2N overexpression alleviated ox-LDL-induced THP-1 macrophage inflammatory response but also alleviated cell foaming. This integrated bioinformatics and experimental study identified five hub genes (HSPB7, MYEF2, DUSP26, TC2N, and PLN) associated with AS. Experimental validation confirmed that TC2N is significantly downregulated in human atherosclerotic plaques and ox-LDL-treated THP-1 macrophages, TC2N overexpression alleviates inflammatory responses and foam cell formation. These findings provide insights into the molecular mechanisms linking aging and immune dysregulation in AS and highlight TC2N as a potential regulator of AS progression.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70382","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835294","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":"Triphala Targets the SLC7A11–GSH–GPX4 Axis to Trigger Ferroptosis in Oral Cancer: An Integrated Network Pharmacology, Molecular Docking, and Experimental Validation Study","authors":"Yiwei Zhao,&nbsp;Simin Li,&nbsp;Linxin Jiang,&nbsp;Deborah Kreher,&nbsp;Gerhard Schmalz,&nbsp;Andreas Fichter,&nbsp;Xianda Hu","doi":"10.1111/cbdd.70375","DOIUrl":"10.1111/cbdd.70375","url":null,"abstract":"<p>Triphala is a traditional three-fruit formulation with potential anticancer activity, but its ferroptosis-related mechanisms in oral cancer remain unclear. We integrated network pharmacology, transcriptomic analyses, prognostic modeling, Mendelian randomization, immune and drug-response analyses, molecular docking, and in vitro validation to investigate the Triphala–ferroptosis–oral cancer axis. Fifty-eight candidate functional genes were identified, and an eight-gene signature comprising AKR1C3, CA9, EGFR, GSTA1, MAPK8, MGST1, PPARG, and RB1 showed prognostic value across multiple cohorts. Mendelian randomization supported causal associations of MAPK8, MGST1, and PPARG with oral cancer risk. Seven Triphala-derived compounds, including epigallocatechin gallate, quercetin, kaempferol, luteolin, ellagic acid, gallic acid, and quinine, displayed favorable predicted interactions with key targets. In CAL-27 cells, Triphala altered the expression of signature genes, reduced GPX4 and SLC7A11 protein levels, increased Fe²⁺and malondialdehyde, depleted glutathione and glutathione peroxidase activity, and enhanced lipid peroxidation; these effects were partially modulated by ferrostatin-1. This study advances the field by linking Triphala to a ferroptosis-based prognostic framework and experimentally demonstrating its regulation of the SLC7A11–GSH–GPX4 axis in oral cancer.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13510106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148820583","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":"Integrative Multi-Omics-Informed Analysis Identifies Insulin Therapy–Associated Loci Implicated in Osteoarthritis Susceptibility","authors":"Lingbo Rong,&nbsp;Jiayong Zhu,&nbsp;Yifan Liu,&nbsp;Tianyu Dai,&nbsp;Liaobin Chen,&nbsp;Hui Wang","doi":"10.1111/cbdd.70384","DOIUrl":"10.1111/cbdd.70384","url":null,"abstract":"<p>Integrative genetic approaches can combine Mendelian randomization, variant annotation, pathway-level interpretation, and exploratory cellular measurements to investigate complex disease mechanisms. However, the relationship between genetic liability to insulin medication use and osteoarthritis (OA) remains incompletely characterized GWAS summary statistics for insulin medication use were obtained from the UK Biobank insulin medication-use dataset. Insulin therapy-associated SNPs were selected using a suggestive significance threshold (<i>p</i> &lt; 5 × 10⁻⁶) and clumped (<i>r</i>² &lt; 0.001, 10,000 kb). Two-sample Mendelian randomization (MR) was performed using the inverse-variance weighted (IVW) method as the primary analysis, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses included Cochran's <i>Q</i> test, MR-Egger intercept, MR-PRESSO global test, and leave-one-out analysis. Insulin-associated genetic variants were functionally annotated using Ensembl VEP, ANNOVAR, FUMA, and Open Targets Genetics, and mapped genes were subjected to exploratory GO biological process and KEGG pathway enrichment analysis. A separate exploratory cellular experiment was performed in the immortalized human chondrocyte cell line TC28a2 using insulin treatment followed by Safranin O staining, RT-qPCR, western blotting, and ELISA. After SNP selection and harmonization, 56 instrument-outcome associations were retained, comprising 29 SNPs in the ukb-a-106 OA dataset and 27 SNPs in the ukb-b-14,486 OA dataset. IVW analysis suggested an association between genetic liability to insulin medication use and increased OA susceptibility (ukb-a-106: OR = 1.195, 95% CI = 1.062–1.344, <i>p</i> = 0.003; ukb-b-14,486: OR = 1.179, 95% CI = 1.066–1.305, <i>p</i> = 0.001). Sensitivity tests did not detect statistically significant heterogeneity or directional horizontal pleiotropy; however, indication-related genetic liability, correlated pleiotropy, and biologically plausible alternative pathways remain important concerns. Seven mapped genes were used for exploratory enrichment analysis. In a separate exploratory cellular experiment, insulin-treated TC28a2 cells under high-glucose conditions showed reduced proteoglycan staining, increased matrix-degrading and inflammatory markers, and reduced NRF2 protein expression. This study suggests an association between genetic liability to insulin medication use and OA susceptibility and provides exploratory functional-annotation and cellular observations for further investigation.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13510103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148820563","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":"Tyrosinase Inhibitors With Enhanced Potency in Mammalian and Vertebrate Models, N-(2-Mercaptoethyl)benzamide Derivatives: Design, Synthesis, and Evaluation","authors":"Hyunhee Ju,&nbsp;Minchang Kim,&nbsp;Hyunju Lee,&nbsp;Hee Jin Jung,&nbsp;Yeonsoo Jeong,&nbsp;Hyejin Kang,&nbsp;Hyeon Seo Park,&nbsp;Hae Young Chung,&nbsp;Hyung Ryong Moon","doi":"10.1111/cbdd.70383","DOIUrl":"10.1111/cbdd.70383","url":null,"abstract":"<p>Retaining structural features that allow 2-mercaptomethylbenzimidazole compounds to function as Cu(II) chelators, <i>N</i>-(2-mercaptoethyl)benzamide (NMEB) derivatives <b>1a</b>–<b>1m</b> were designed, synthesized, and assessed for their potential as Cu(II) chelators. Derivative <b>1m</b> inhibited mushroom tyrosinase (mTYR) activity twice as potently as kojic acid (KA) in the presence of <span>l</span>-DOPA. The mechanisms by which three derivatives, including <b>1m</b>, inhibit mTYR were elucidated through kinetic studies. Interestingly, all NMEB derivatives suppressed melanogenesis more potently than KA in B16F10 cells, significantly reducing melanin production in a concentration-dependent manner. NMEB derivatives also inhibited cellular TYR activity in keeping with their melanogenesis inhibition, indicating B16F10 cellular TYR inhibition to be the primary mechanism. Moreover, among these derivatives, <b>1a</b> inhibited zebrafish larval pigmentation hundreds of times more potently than KA. In mammalian cells and zebrafish larvae, NMEB derivatives showed even higher TYR-inhibitory or antimelanogenesis potency than mushrooms. Due to differences in the amino acid sequence and location of TYRs, NMEB derivatives appear to differ in their inhibition of TYR activity and melanin production in different species. This study points out limitations in the development of novel TYR inhibitors based on mTYR inhibition results and provides fundamental data supporting their development as novel skin-lightening agents.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809605","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":"Chemical and Structural Engineering of Guide RNAs for Precision Genome Editing: From Design Principles to Clinical Applications","authors":"Masaki Kawamata,&nbsp;Satoshi Niwa,&nbsp;Atsushi Suzuki","doi":"10.1111/cbdd.70377","DOIUrl":"10.1111/cbdd.70377","url":null,"abstract":"<p>CRISPR–Cas9 has revolutionised genome editing by enabling efficient and programmable modification of defined DNA sequences, with guide RNAs (gRNAs) serving as indispensable elements that direct Cas9 to specific genomic loci. Initially regarded as auxiliary components, gRNAs are now recognized as critical determinants of editing efficiency and specificity and have attracted growing attention as independent targets for engineering. Chemical modification, sequence optimisation, and structural alteration of gRNAs have been shown to enhance on-target activity, suppress off-target effects and cytotoxicity, and even achieve allele-selective precision editing in a programmable manner. Moreover, advances in artificial intelligence and machine learning have markedly improved the predictive accuracy of gRNA design through large-scale data analysis. Despite rapid progress, a consolidated review that integrates chemical, structural, and computational advances in gRNA engineering and highlights their translational potential for therapeutic genome editing has been lacking. This review uniquely addresses that gap by presenting an integrated framework that connects molecular design principles with clinical applicability.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809582","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":"Dual-Targeting, Hybrid Antifungal Agents Targeting Candida albicans—An Overview","authors":"Sarmistha Pal,&nbsp;Sriparna Pusti,&nbsp;Iftakhar Hussain Ansari,&nbsp;Sanchita Pradhan,&nbsp;Hritabrata Bhattacharya,&nbsp;Shuvradip Das","doi":"10.1111/cbdd.70380","DOIUrl":"https://doi.org/10.1111/cbdd.70380","url":null,"abstract":"<p>Due to environmental degradation, substance abuse, and immunological loss, fungal diseases are rising. <i>Candida</i> sp. can inflame tissues and organs. In addition, fungi enter deep tissues to generate invasive fungal infections (IFIs), a long-term worldwide health risk, especially for HIV/chemotherapy patients with compromised immune systems. The present treatment uses single-target antifungals like azoles, allylamines, and pyrimidines. But drug-resistant fungi and widespread adverse effects have limited their therapeutic efficacy. Thus, innovative, safe, and effective antifungals are needed. Through the 20th century, the pharmaceutical industry adopted the “one molecule, one target, one disease” mentality which led to various effective selective drugs that will dominate disease treatment. But, unfortunately, even with the best research, targeting one target may not work in complicated illnesses. Thus, drugs that activate several targets simultaneously, to improve efficacy and safety, are gaining interest. Multitarget medicines involve monotherapies, medication cocktails, and combination drugs. The second method, multitarget-directed ligands (MTDLs), uses one active component that treats multifactorial diseases. In MTDL, new chemical entities (NCEs) are created which may solve various issues related to combination therapies, including: (1) establishing balanced and multi-selective potency across targets, (2) matching PK/PD properties for components, (3) better patient compliance, (4) straightforward approval from regulatory authorities, (5) higher cost of medication etc. To optimize developability, effectiveness, and safety, multitarget drug design should be more methodical and thorough in target combinations, ligand selection, and desired activity equilibrium. In this review, the hybrid, dual-targeting antifungal agents are classified into four major categories, based on the combination of their mechanisms, namely—(<b>1</b>) Antifungal + antifungal (involves dual mode of DNA damage + membrane polarization), (<b>2</b>) Antifungal + Resistance reversal (includes proteasome inhibition, Coumarin + CYP51 inhibitors, CYP51 + Hsp90 inhibitors), (<b>3</b>) Antifungal + Host immunity modulators (includes CYP51 + HDAC inhibitors, NLRP3 inflammasome + AHAS inhibitors, COX + CYP51 inhibitors, PD-L1 + CYP51 inhibition etc.), (<b>4</b>) Azole sensitisers (JAK2 + HDAC inhibition, BRD4 + HDAC inhibition etc.), (<b>5</b>) Multifunctional, miscellaneous antifungal agents (DNA intercalation + intracellular ROS production) etc. Thus, it covers significant achievements and the associated challenges of antifungal multitarget drug design, which might be helpful to the researchers who are interested in delving into the development of fungicidal agents as a drug to address the burning question of drug-resistant <i>Candida albicans</i> and invasive fungal infections (IFIs).</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70380","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784491","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":"Multi-Omics-Guided Design and Safety Engineering of Nucleic Acid Therapeutics: From Molecular Perturbation to Predictive Toxicology and Precision Translation","authors":"Gurjit Kaur Bhatti,&nbsp;Anushka Verma,&nbsp;Komal Devi,&nbsp;Naina Khullar,&nbsp;Inderpal Singh Sidhu,&nbsp;Umesh Chand Singh Yadav,&nbsp;Jasvinder Singh Bhatti","doi":"10.1111/cbdd.70378","DOIUrl":"https://doi.org/10.1111/cbdd.70378","url":null,"abstract":"<p>Nucleic Acid Therapeutics (NATs), including Antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and messenger RNAs (mRNAs), are a rapidly developing class of therapeutics capable of specifically regulating previously considered undruggable and inaccessible genes and pathways for modification by small molecules and antibodies. Despite promising results, the utilization of NATs in clinical practice is complicated by the potential off-target effects, such as activation of the immune response and organ-specific toxicity, which cannot be effectively predicted based solely on primary structure, chemotype descriptors, or off-target effects predictors developed in silico. A combination of multiple omics technologies, including proteomics/metabolomics/single-cell transcriptomics, helps researchers elucidate the interaction of drug compounds with biological targets. This allows for the detection of changes not only at the pathway and cellular level but also early signs of toxicity in parallel. Thus, in this context, this review offers a mechanistic view on the use of multi-omics strategies for the investigation of NATs-induced biological effects to analyze the mechanism of action of chemically modified ASOs, siRNAs and mRNA conjugates. The review also discusses case studies in which multi-omics data have been used to improve therapeutic development. By examining individual layers of molecules separately, a more holistic understanding of treatment mechanisms can be achieved, which is helpful for the discovery of biomarkers and the development of next-generation nucleic acid drugs.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70378","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784170","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":"Multi-Omics Integration Identifies PTGS2 as a Candidate Diagnostic Biomarker and Precise Therapeutic Target Related to Schisandra chinensis for Osteoarthritis","authors":"Lingtian Min,&nbsp;Yikai You,&nbsp;Shiqi Ren,&nbsp;Cheng Chen","doi":"10.1111/cbdd.70368","DOIUrl":"10.1111/cbdd.70368","url":null,"abstract":"<p>Currently, there is a lack of effective disease-modifying drugs for osteoarthritis (OA), and existing treatment methods often accompany significant adverse reactions. <i>Schisandra chinensis</i> (SC), as a traditional Chinese medicine with anti-inflammatory activity, may have therapeutic potential for OA, but its specific molecular mechanism is not yet clear. This study adopts network pharmacology strategy to explore the potential mechanism of SC intervention in OA. Screen SC active ingredients through TCMSP database and obtain OA-related targets by combining OMIM, TTD, and GeneCards databases. Venn analysis shows that there are only 5 common targets between SC and OA; Further analysis revealed that PTGS2 is the only candidate target with diagnostic value (AUC = 0.702, <i>p</i> = 0.015), while AR, ESR1, DPP4, and CHRM2 did not show clinical diagnostic efficacy. Functional enrichment analysis suggests that common targets mainly involve steroid hormone responses and extracellular matrix (ECM) related pathways, with a significant enrichment in “response to steroid hormones” (adjusted <i>p</i> = 1.2 × 10 ⁻⁵), and GSEA also shows activation of the ECM-receptor interaction pathway (NES = 1.87, <i>p</i> = 0.002). The molecular docking results indicate that the SC active ingredients MOL008957 and MOL008978 can form stable binding with PTGS2. The qRT-PCR results further confirmed that the expression of PTGS2 was significantly downregulated in the OA model after SC intervention. Single cell transcriptome analysis showed that PTGS2 was mainly enriched in monocytes and gradually increased with the pseudo temporal progression; Cell communication analysis revealed that monocytes can interact with NK cells and T cells through the MIF-CD74 + CXCR4 and MIF-CD74 + CD44 signaling axes. After virtual knockout of PTGS2, downstream regulatory networks suggest that GSN may be a key target gene, mainly involving collagen containing extracellular matrix and ECM structural components. In summary, SC may exert its anti OA effect mainly by selectively inhibiting PTGS2 and maintaining the homeostasis of ECM related pathways. PTGS2 is expected to become a candidate biomarker for OA and a potential target for SC intervention in OA, but further experimental verification of the specific efficacy and mechanism of SC active ingredients is still needed.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70368","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148762831","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":"Single-Cell and Bulk Transcriptomics Identify GNGT1-High Malignant Epithelial Cells Associated With Immune Suppression in Esophageal Squamous Cell Carcinoma","authors":"Qian Yuan,&nbsp;Cheng Wang,&nbsp;Yintao Chang,&nbsp;Qiang Lyu,&nbsp;Yuxiang Jin,&nbsp;Lei Xue","doi":"10.1111/cbdd.70381","DOIUrl":"10.1111/cbdd.70381","url":null,"abstract":"<p>Esophageal squamous cell carcinoma (ESCC) features epithelial heterogeneity and an immunosuppressive microenvironment, yet clinically relevant malignant epithelial states remain poorly defined. We integrated four single-cell RNA-sequencing datasets and 10 bulk transcriptomic cohorts totaling 1318 samples, and applied cross-cohort differential expression, survival analysis, and a machine-learning framework of 113 algorithm combinations to screen for malignant epithelial cell-associated biomarkers. GNGT1 was prioritized for its consistent upregulation, prognostic association, and limited prior characterization in ESCC. Across independent cohorts, GNGT1 exhibited favorable diagnostic performance, while high expression correlated with poorer overall survival and more advanced local tumor status. Immune deconvolution consistently linked GNGT1-high tumors to reduced CD8⁺ T-cell infiltration, lower immune scores, and decreased cytotoxic T-cell markers. Single-cell analyses further associated GNGT1-high epithelial cells with altered epithelial–immune communication involving MIF, prostaglandin, and CXCL signaling, alongside enrichment of epithelial–mesenchymal transition, mTORC1, and proliferative programs; qPCR confirmed elevated GNGT1 expression in ESCC cell lines. This study defines GNGT1 as a marker of an immunosuppressive malignant epithelial state, thereby bridging epithelial heterogeneity with immune remodeling in ESCC. These findings support GNGT1 as a candidate diagnostic, prognostic, and biologically informative biomarker warranting mechanistic and clinical validation.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70381","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148727592","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}