Chemical Biology & Drug Design最新文献

{"title":"Design, Synthesis of Novel Quinazolinone Derivatives and Evaluation of EGFR Kinase Inhibition Activity via In Vitro and In Silico Studies","authors":"Aybüke Züleyha Kaya,&nbsp;Asaf Evrim Evren,&nbsp;Gülşen Akalın-Çiftçi,&nbsp;Leyla Yurttaş","doi":"10.1111/cbdd.70338","DOIUrl":"10.1111/cbdd.70338","url":null,"abstract":"<p>Cancer is one of the most seen diseases worldwide. Due to the serious side effects of anticancer drugs and toxic effects on healthy cells, investigations for novel anticancer agents with low side effects have become one of the most important research areas of our age. With this objective, 17 new compounds were designed and successfully synthesized based on the quinazolinone, which is commonly found in the structures of FDA-approved EGFR inhibitors, and their structures were elucidated by IR, HRMS, ¹H, and ¹³C-NMR spectral analysis methods. According to cytotoxicity test results, it was determined that compound <b>4j</b> showed high inhibitory activity compared to cisplatin and gefitinib in the A549 cell line. In apoptosis induction studies, it was observed that compounds <b>4a</b>, <b>4b</b>, <b>4d</b>, and <b>4f</b> showed activity in the A549 cell line, while compound <b>4j</b> showed activity in the MCF-7 cell line. In the study investigating caspase-3 activation, compounds <b>4a</b>, <b>4m</b>, and <b>4o</b> were found active in the A549 cell line, while compounds <b>4a</b> and <b>4o</b> were found active in MCF-7 cells. In EGFR enzyme inhibition studies, it was observed that the activities of molecules <b>4b</b>, <b>4f</b>, and <b>4j</b> were higher than gefitinib. In silico studies indicated that <b>4j</b> interacted by establishing significant bonds with both caspase-3 and EGFR enzyme.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70338","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148280444","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":"Revealing the Action Mechanism of the FOXA2-LAMC2 Axis in Driving Cisplatin Resistance of Head and Neck Squamous Cell Carcinoma via Based Multi-Omic Analysis and Experimental Validation","authors":"Caihong Liang,&nbsp;Hengtao Zhu,&nbsp;Yunfei Gao,&nbsp;Shuyue Yu,&nbsp;Guangda Liang,&nbsp;Cunyu Miao,&nbsp;Junjing Zhang,&nbsp;Hongqun Jiang","doi":"10.1111/cbdd.70328","DOIUrl":"10.1111/cbdd.70328","url":null,"abstract":"<div>\u0000 \u0000 <p>Cisplatin is a key treatment for head and neck squamous cell carcinoma (HNSCC), but the development of resistance severely limits its effectiveness. The molecular determinants underlying cisplatin resistance in HNSCC remain unclear. Multiple databases were used to screen the core genes related to cisplatin resistance in HNSCC patients. Tumor tissue samples from HNSCC patients were collected and the expression of FOXA2 was verified through various pathological tests to establish the correlation between FOXA2 expression and the clinical characteristics of the patients. The in vitro and patient-derived organoids (PDOs) models were used to verify the regulatory effect of FOXA2 on the cisplatin resistance of HNSCC. Transcriptome sequencing combined with multi-omics analysis demonstrated that LAMC2 is a downstream target of FOXA2 in regulating cisplatin resistance. Bioinformatic screening of cisplatin-resistant cohorts revealed that FOXA2 was the only gene significantly associated with poor survival outcomes in TCGA-HNSCC patients. Transcriptomic profiling and pathway enrichment analyses revealed the activation of the PI3K/AKT signaling cascade. We identified LAMC2 as a direct transcriptional target of FOXA2. Chromatin immunoprecipitation and luciferase reporter assays confirmed FOXA2 binding to the LAMC2 promoter, resulting in transcriptional activation. FOXA2-mediated upregulation of LAMC2 increased PI3K and AKT phosphorylation, and LAMC2 overexpression reversed the impaired malignant phenotypes caused by FOXA2 silencing. In xenograft models and PDO systems, FOXA2 overexpression reduced responsiveness to cisplatin, whereas FOXA2 inhibition significantly increased therapeutic sensitivity. Our research has identified a previously unrecognized regulatory axis involving FOXA2, LAMC2, and PI3K/AKT, which plays a crucial role in the progression and resistance to cisplatin in HNSCC. Therefore, targeting the FOXA2-LAMC2 axis may represent a novel therapeutic strategy to overcome cisplatin resistance in HNSCC.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148280455","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 Overview of Panobinostat: Pharmacological and Medicinal Chemistry Aspects","authors":"Ajam C. Shaikh,&nbsp;Swastika Banerjee,&nbsp;Vijay Bahadur,&nbsp;Pravin R. Bhansali","doi":"10.1111/cbdd.70330","DOIUrl":"10.1111/cbdd.70330","url":null,"abstract":"<div>\u0000 \u0000 <p>Panobinostat, a potent histone deacetylase inhibitor (HDACi), has been studied for epigenetic control and cancer treatment. It impacts chromatin remodeling, gene transcription, and protein degradation, leading to the progression of the cell cycle and death. This review extensively analyses panobinostat's pharmacological and medicinal chemistry characteristics, including its mode of action, structure–activity relationship, metabolism, synthesis, and repurposing. Current research shows panobinostat to be effective for nononcological indications such as neurological disorders, HIV latency reversal, and fetal haemoglobin reactivation. This review highlights the necessity for continued SAR investigations to improve isoform selectivity and examines the growing clinical applications of panobinostat beyond oncology.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148274209","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":"Optimization of Deep Eutectic Solvent Extraction Process and Study on the Anti-Alcoholic Fatty Liver Disease Activity and Mechanism of Flavonoids From Lophatherum gracile Brongn.","authors":"Yuyue Luo,&nbsp;Ling Yan,&nbsp;Jinghan Jia,&nbsp;Hongyu Wang,&nbsp;Mengxuan Zhang,&nbsp;Jie Qin,&nbsp;Wenlong Sun","doi":"10.1111/cbdd.70323","DOIUrl":"10.1111/cbdd.70323","url":null,"abstract":"<div>\u0000 \u0000 <p>Deep eutectic solvents (DESs) are a novel type of green extraction medium characterized by strong designability, biodegradability, and high extraction efficiency, making them highly promising for the separation of bioactive components from natural products. <i>Lophatherum gracile Brongn</i>. (<i>L. gracile</i>) is rich in various bioactive components, including flavonoids and polysaccharides. This study established a DES-based extraction system for flavonoids of <i>L. gracile</i>, optimized the process using response surface methodology, and evaluated the antioxidant activity, and hepatoprotective effects of the extracts against alcoholic liver disease (ALD) with focus on gut microbiota modulation. A choline chloride-malic acid DES was identified as the optimal extractant. Under the optimized conditions (extraction time of 60 min, water content of 32%, liquid-to-solid ratio of 61:1 mL/g, molar ratio of 1:1, ultrasonic power of 480 W, and temperature of 60°C), the extraction yield of <i>L. gracile</i> flavonoids reached 16.62 ± 0.27 mg/g. Compared to traditional ethanol extracts, the DES-extracted <i>L. gracile</i> flavonoids exhibited significantly stronger DPPH radical scavenging activity. Moreover, they demonstrated enhanced hepatoprotective effects in an ALD mouse model by ameliorating dyslipidemia, alleviating liver injury, and improving hepatic histopathology. Notably, the DES extracts more effectively reshaped the alcohol-disrupted gut microbiota by increasing beneficial bacteria (e.g., <i>Akkermansia</i> and <i>Lactobacillus</i>) while suppressing pathogenic genera (e.g., <i>Escherichia-Shigella</i> and <i>Bacteroides</i>). These findings provide an efficient and environmentally friendly extraction strategy for <i>L. gracile</i> flavonoids and offer experimental evidence for their potential application in alcoholic liver disease prevention and treatment through gut microbiota modulation.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148254925","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":"Cruzain Inhibitors for Chagas Disease: Anticorrelated Optimisation Landscapes and the Multiparametric Path to Clinical Candidates","authors":"Caroline Rodrigues Chaves dos Reis,&nbsp;Hellen Valério Chaves Moura de Souza,&nbsp;Lidia Corrêa Parra,&nbsp;Guilber Valério Chaves Moura de Souza,&nbsp;Bruna Costa Zorzanelli,&nbsp;Nubia Boechat,&nbsp;Lucas Villas Bôas Hoelz,&nbsp;Tácio Vinício Amorim Fernandes","doi":"10.1111/cbdd.70340","DOIUrl":"10.1111/cbdd.70340","url":null,"abstract":"<p>Over three decades, cruzain, the principal cysteine protease of <i>Trypanosoma cruzi</i> and a validated drug target for Chagas disease, has accumulated 215 inhibitors with IC₅₀ ≤ 1 μM, more than 30 crystal structures, and no clinical candidates. This review argues that the resulting translational paradox reflects not target invalidity, but a persistent strategic mismatch between how cruzain inhibitors have been optimised and what intracellular efficacy requires. Across peptidyl vinyl sulfones, non-peptidic scaffolds, and thiosemicarbazones, enzymatic potency has been systematically prioritised over the coupled determinants of intracellular exposure: permeability, metabolic stability, and cathepsin selectivity. Each inhibitor class fails for a distinct proximal reason, and these failures converge on the same optimisation bias. Computational approaches (docking, molecular dynamics, free-energy perturbation and machine-learning QSAR) have been applied with increasing sophistication, but against affinity-centred objectives that underrepresent exposure constraints. As its principal contribution, this work proposes a multiparametric optimisation framework, provisional viability benchmarks, and a feasibility-envelope concept that reframes cruzain inhibitor discovery as a constraint-satisfaction rather than a potency-maximisation problem. The framework outlines provisional quantitative criteria that a next-generation cruzain lead would likely need to satisfy and explains why structurally tractable intracellular cysteine protease targets can remain clinically unrealised.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70340","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148255008","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":"Saponarin: Therapeutic Potential, Pharmacological Insights, and Future Directions","authors":"Mohammed A. Abdel-Rasol,&nbsp;Wael M. El-Sayed","doi":"10.1111/cbdd.70339","DOIUrl":"https://doi.org/10.1111/cbdd.70339","url":null,"abstract":"<div>\u0000 \u0000 <p>Saponarin, a flavonoid glycoside, has demonstrated various pharmacological effects in preclinical systems, including antioxidant, anti-inflammatory, hepatoprotective, neuroprotective, anticancer, and cardioprotective properties. These effects are attributed to its modulation of key signaling pathways such as Nrf2, NF-κB, PI3K/Akt, MAPK, and TGF-β. However, the translational relevance of these interactions remains unestablished in human subjects. This review consolidates findings on saponarin's mechanisms of action and therapeutic potential, focusing primarily on in vitro and animal model evidence, while highlighting gaps that limit its clinical applicability across liver diseases, neurodegenerative conditions, cancer, diabetes, and cardiovascular diseases. In hepatic disease models, saponarin has shown potential in reducing oxidative stress markers, attenuating liver fibrosis, and improving mitochondrial function, indicating its relevance to non-alcoholic fatty liver disease, alcoholic liver disease, and drug-induced liver injury. However, these findings have not been confirmed in human trials, and the translation of rodent hepatoprotective data to humans remains uncertain. In neurodegenerative models, saponarin reduced β-amyloid deposition and tau hyperphosphorylation. However, poor blood–brain barrier penetration and the lack of human validation limit the therapeutic relevance for Alzheimer's and Parkinson's diseases. In cancer models, saponarin inhibited proliferation, induced apoptosis, suppressed metastatic markers, and reduced angiogenic signaling. However, cancer cell line sensitivity often fails to predict in vivo efficacy, and no clinical evidence supports its use as adjunctive cancer therapy. Limited preclinical evidence also suggests potential effects on insulin sensitivity, glycemic regulation, and cardiovascular parameters, but human studies are absent. Despite these promising findings, saponarin lacks clinical validation. Most effects come from in vitro and animal models, which exhibit variability in experimental conditions, doses, and formulations, limiting definitive conclusions. Saponarin's poor oral bioavailability, absence of standardized formulations, restricted blood–brain barrier penetration, and lack of long-term safety data present significant barriers to development. Although novel delivery methods such as nanoparticles and liposomal formulations have been proposed to improve pharmacokinetics, they remain experimental and unvalidated in humans. Future research should focus on rigorous clinical trials to assess whether preclinical findings translate to clinically meaningful outcomes, alongside comprehensive pharmacokinetic and safety evaluations in humans. Until then, saponarin should be regarded as an experimental compound with preliminary preclinical findings, rather than a clinically recommended therapeutic agent.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238162","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":"Ginkgetin Attenuates Dextran Sulfate Sodium-Induced Colitis by Inhibiting the Nuclear Factor Kappa B Pathway","authors":"Xuejing Qiao,&nbsp;Wei Xie,&nbsp;Yanfei Ding,&nbsp;Lianmei Shan","doi":"10.1111/cbdd.70341","DOIUrl":"https://doi.org/10.1111/cbdd.70341","url":null,"abstract":"<div>\u0000 \u0000 <p>Ginkgetin is a biflavone isolated from <i>Ginkgo biloba</i> leaves. It has shown anti-inflammatory effects in colitis. However, its molecular mechanisms remain unclear. This study investigated the therapeutic effects of ginkgetin on dextran sulfate sodium (DSS)-induced colitis in mice and lipopolysaccharide (LPS)-treated Caco-2 cells. Inflammation, the integrity of the colonic epithelial barrier, and cellular damage were assessed via immunofluorescence, reverse transcription quantitative polymerase chain reaction, and Western blotting. Furthermore, p65 was overexpressed or knocked down to examine its involvement in the observed effects. Treatment with ginkgetin significantly attenuated weight loss, disease activity index, and histopathological damage in DSS-induced mice. It also downregulated pro-inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), and upregulated tight junction proteins, such as zonula occludens-1 (ZO-1) and Occludin, in vivo and in vitro. Notably, ginkgetin inhibited p-p65 and C-X-C motif chemokine ligand 2 in colonic tissues and Caco-2 cells. Molecular docking, biotin pull-down, and cellular thermal shift assays suggested an interaction between ginkgetin and p65. p65 overexpression reversed the inhibitory effects of ginkgetin on LPS-induced inflammation and barrier disruption. p65 knockdown normalized LPS-induced alterations, downregulated pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β), and upregulated tight junction proteins (ZO-1 and Occludin). Notably, the addition of ginkgetin did not further improve the beneficial effects of p65 knockdown alone. These findings suggest that ginkgetin alleviated colitis by modulating inflammation and epithelial barrier dysfunction through the nuclear factor kappa B pathway. This study demonstrates the potential of ginkgetin as a therapeutic agent for colitis.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238161","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 and Pharmacological Evaluation of 4H-Chromene-3-Carbonitrile Derivatives as Antiplatelet Agents","authors":"Afsoon Feizi,&nbsp;Mahvand Oraji,&nbsp;Mona Khoramjouy,&nbsp;Mohammadsaeed Kordi,&nbsp;Salimeh Amidi,&nbsp;Marjan Esfahanizadeh,&nbsp;Ali Almasirad,&nbsp;Farzad Kobarfard","doi":"10.1111/cbdd.70311","DOIUrl":"10.1111/cbdd.70311","url":null,"abstract":"<div>\u0000 \u0000 <p>A series of 4<i>H</i>-Chromene-3-carbonitrile derivatives was synthesized, and their in vitro antiplatelet activities were evaluated against arachidonic acid (AA) and adenosine diphosphate (ADP) in plasma. Among the synthesized compounds, 4<i>H</i>-Chromene-3-carbonitrile derivative with a 4-methoxy group (<b>4j</b>) exhibited the most potent antiplatelet activity against AA-induced aggregation. Almost no activity was observed against the aggregation induced by ADP. Additionally, the in vivo antiplatelet activity of the most potent compound was evaluated using bleeding time and aggregation tests in rats. Compound <b>4j</b> showed antiplatelet activities in both the oral and intravenous routes of administration in bleeding time and aggregation tests. Notably, the effects were comparable with indomethacin. The structure–activity relationship (SAR) study suggested that the antiplatelet activity of the compound might be governed by the electronic properties of the substituent on the ring of the derivative. The electron-donating groups at the 4′ position resulted in the most active derivative. Our results show that compound <b>4j</b> may be an appropriate compound for future investigations in the field of antiplatelet drug discovery.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148221286","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 Integration Reveals Incomplete Reactivation of Developmental Cell-Cycle Programs in Adult Human Infarcted Hearts","authors":"Jieran Lyu,&nbsp;Yuki Kuramoto,&nbsp;Jun Li,&nbsp;Jong-Kook Lee,&nbsp;Kyoko Hidaka,&nbsp;Yasushi Sakata","doi":"10.1111/cbdd.70337","DOIUrl":"10.1111/cbdd.70337","url":null,"abstract":"<p>Adult human hearts show limited regeneration after acute myocardial infarction (AMI) despite a small subpopulation (~5%) of cardiomyocytes re-entering the cell cycle. We integrated public single-nucleus RNA-seq, spatial transcriptomics, bulk RNA-seq and ATAC-seq datasets from human fetal hearts and adult infarcted hearts to investigate why cell-cycle-active cardiomyocytes fail to complete division. These cells were enriched in the infarct zone (IZ) and activated early cell-cycle programs, but showed insufficient reactivation of late mitotic and cytokinesis execution machinery, particularly <i>ANLN</i> and <i>KIF18A</i>, and instead engaged stress-adaptive programs. Multi-omics filtering across expression, chromatin accessibility, and co-expression/regulatory networks highlighted five developmental cell-cycle-associated genes with insufficient adult reactivation: <i>ANLN</i>, <i>KIF18A</i>, <i>MDK</i>, <i>RTKN2</i>, and <i>SOX11</i>. In human induced pluripotent stem cell-derived cardiomyocytes, hypoxia suppressed most candidates, whereas <i>MDK</i> retained responsiveness to pro-proliferative Wnt stimulation. These findings suggest that incomplete cytokinesis reactivation represents a key bottleneck for adult human cardiac regeneration, and nominate <i>MDK</i> as a tractable candidate for chemical biology and drug-discovery efforts aimed at promoting cardiomyocyte cell-cycle completion.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70337","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148207176","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":"Integrated Single-Cell and Machine Learning Analysis Identifies Fibroblast-Associated Hub Genes and Potential Therapeutics in Ischemic Cardiomyopathy","authors":"Gaoxiu Yu,&nbsp;Tong Kan,&nbsp;Jian Shen,&nbsp;Yanming Zhang,&nbsp;Cong Wang,&nbsp;Zhifu Guo,&nbsp;Feng Chen","doi":"10.1111/cbdd.70329","DOIUrl":"https://doi.org/10.1111/cbdd.70329","url":null,"abstract":"<div>\u0000 \u0000 <p>Ischemic cardiomyopathy (ICM), a leading cause of heart failure, is characterised by complex cellular heterogeneity and a dysregulated microenvironment. A systematic computational dissection of its molecular mechanisms and a coherent pipeline from discovery to potential therapeutics is currently lacking. We integrated single-cell RNA sequencing (scRNA-seq) data from ICM patients with four independent bulk transcriptomic cohorts. A cardiac cellular atlas was constructed, and candidate genes were filtered through differential expression analysis. Subsequently, a benchmark of 127 machine learning algorithm-feature selection combinations was performed to identify robust diagnostic hub genes. Their functions were validated at single-cell resolution via UCell scoring, pseudotime trajectory analysis, and virtual knockout perturbations using scTenifoldKnk. The immune infiltration landscape was assessed using CIBERSORT and MCP-counter. Finally, computational drug repositioning and molecular docking were employed to screen for potential compounds targeting the hub genes. Machine learning identified a core 5-gene signature (<i>NPPA, HTRA1, LUM, ASPN</i>, and <i>OGN</i>) demonstrating excellent diagnostic performance across independent datasets (AUC &gt; 0.83). Single-cell analysis revealed that these genes were most abundantly expressed in fibroblasts and were consistently upregulated in ICM. Pseudotemporal trajectory analysis illustrated their dynamic expression patterns. Virtual knockout and functional enrichment indicated that four of these genes (<i>ASPN, HTRA1, LUM, OGN</i>) significantly perturbed pathways related to the regulation of inflammatory response. Immune profiling revealed increased infiltration of fibroblasts and plasma cells in ICM. Molecular docking identified the compound LDN-193189 as a potential lead molecule with high predicted binding affinity (binding energy &lt; −9 kcal·mol⁻¹) for <i>ASPN, LUM</i>, and <i>OGN</i>. Through multi-omics integration and computational biology, this study systematically delineates a fibroblast-centric molecular network involving key hub genes and an altered immune microenvironment in ICM and computationally proposes a potential therapeutic candidate. These findings provide a crucial computational foundation and experimental direction for understanding ICM pathology and developing novel therapeutic strategies.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148174300","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}