Chemical Biology & Drug Design最新文献

{"title":"Emerging Roles of Osmium Complexes in Cancer Therapy, Their Mechanism of Action, Challenges and Future Perspectives","authors":"Eman M. Atiyah,&nbsp;Duha Majeed Hasan,&nbsp;Ahmad H. Ibrahim,&nbsp;Sawsan S. Al-Rawi,&nbsp;Ghazala Iram,&nbsp;Sadia Aziz,&nbsp;Muhammad Adnan Iqbal","doi":"10.1111/cbdd.70248","DOIUrl":"10.1111/cbdd.70248","url":null,"abstract":"<div>\u0000 \u0000 <p>Since cisplatin was discovered and used as an anti-cancer agent in clinical settings, research into cancer treatments has revealed a number of possible drugs based on metal-containing scaffolds. This has produced a large number of metallodrugs suitable for use in medicine. The roles and mechanisms of action of these metallodrugs are more diverse than those of pure organic compounds. Since they demonstrated efficacy against numerous cancer cell lines, metallodrugs based on osmium are among the most researched and produced substitutes for platinum-based anti-cancer drugs. The metal-based drugs are a new, well-developed type of drug in anticancer therapy with specific mechanisms of action that are much different from the organic chemical drugs used in chemotherapy. They have the potential to disrupt cellular processes necessary for the survival and growth of cancer cells since they are able to interact with a variety of biological targets such as DNA, proteins, and enzymes. This review article focuses on the role of Os-complexes in cancer treatment, their mechanism of action, challenges, and future perspectives of Os-complexes in cancer therapy.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133803","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 Antiproliferative Pyrazole/Quinoline Hybrids: Design, Synthesis, and Biological Evaluation as EGFR Inhibitors","authors":"Mai E. Shoman,&nbsp;Heba A. Hassan,&nbsp;Hesham A. M. Gomaa,&nbsp;Bahaa G. M. Youssif,&nbsp;Rania B. Bakr,&nbsp;Samar H. Abbas","doi":"10.1111/cbdd.70256","DOIUrl":"10.1111/cbdd.70256","url":null,"abstract":"<div>\u0000 \u0000 <p>A series of new pyrazole/quinoline hybrids <b>11a–n</b> was constructed and synthesized as prospective antiproliferative agents. The antiproliferative activities of the newly synthesized hybrids were assessed against a panel of four human cancer cells: HT-29, A-549, Panc-1, and MCF-7. Hybrids <b>11c</b>, <b>11d</b>, <b>11h</b>, <b>11i</b>, and <b>11k</b> demonstrated remarkable antiproliferative activity, with IC₅₀ ranging from 36 to 61 nM, compared to erlotinib, which had IC₅₀ ranging from 30 to 40 nM. Hybrid <b>11i</b> was the most potent EGFR inhibitor with an IC₅₀ of 87 nM and exhibited comparable EGFR inhibition to that of erlotinib (IC₅₀ = 80 nM). Molecular docking study results in the EGFR active site agreed with the EGFR inhibitory activity results.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146121271","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":"The Therapeutic Effect and Mechanism of Vismodegib on COPD: Focusing on NETs and Macrophage Polarization","authors":"Ming Wu,&nbsp;Chao Quan,&nbsp;Li Yao,&nbsp;Yanna Yang,&nbsp;Junhui Liu,&nbsp;Qi Zhu","doi":"10.1111/cbdd.70258","DOIUrl":"10.1111/cbdd.70258","url":null,"abstract":"<div>\u0000 \u0000 <p>The Hedgehog pathway may be involved in chronic obstructive pulmonary disease (COPD). Its inhibitor, Vismodegib, has therapeutic potential, but the underlying mechanisms require further investigation. A COPD mouse model was established using lipopolysaccharide (LPS) and cigarette smoke exposure, with concurrent Vismodegib intervention. Assessments included histopathology, pulmonary function, inflammatory cytokines, neutrophil extracellular traps (NETs) markers, macrophage polarization, and integrated transcriptomic and gut microbiota (16S rRNA) analysis. The results show that Vismodegib alleviated lung injury and fibrosis, regulated the respiratory rate, reduced the levels of pro-inflammatory cytokines such as interleukin (IL)-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α), promoted a phenotypic shift from M1 to M2 macrophage polarization, and suppressed NETs formation, as demonstrated by decreased levels of neutrophil elastase (NE), citrullinated histone H3 (Cit-H3), myeloperoxidase (MPO), and Cit-H3⁺Ly6G⁺ cells. Multi-omics analysis revealed enrichment of the IL-17 signaling pathway and increased gut microbial abundance of <i>Bacteroidaceae</i> and <i>Tannerellaceae</i>. Vismodegib may alleviate inflammation and tissue damage in COPD by inhibiting NETs-mediated M1 polarization of macrophages. This study is the first to propose the targeting of NET-driven macrophage polarization via Hedgehog inhibition as a novel therapeutic strategy for COPD, providing a new mechanistic framework for drug repurposing.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146121269","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":"From Synthesis to Efficacy: Synthesis, Structural Analysis, and Antiviral Activity of 5-(Trifluoromethoxy)-1H-indole-2,3-dione 3-Thiosemicarbazones","authors":"Özge Soylu-Eter,&nbsp;Leentje Persoons,&nbsp;Lieve Naesens,&nbsp;Nilgün Karalı","doi":"10.1111/cbdd.70259","DOIUrl":"10.1111/cbdd.70259","url":null,"abstract":"<div>\u0000 \u0000 <p>Viral infections are a global cause of serious morbidity and mortality. The recent COVID-19 pandemic further testifies to the continued need to develop novel classes of antiviral agents with broad activity and high selectivity. In this work, 5-(trifluoromethoxy)-1<i>H</i>-indole-2,3-dione 3-(4-phenylthiosemicarbazones) bearing a methyl or ethyl group at position 1- of the indole ring were synthesized. Along with previously synthesized compounds <b>5a-j</b>, <b>5l</b>, <b>6b-d</b>, <b>6g</b>, <b>6i</b>, and <b>6k-n</b>, the novel compounds <b>5k</b>, <b>6a</b>, <b>6e</b>, <b>6f</b>, <b>6h</b>, <b>6j</b>, and <b>6o</b> were evaluated in cytopathic effect (CPE) reduction assays with a broad range of DNA and RNA viruses. Favorable activity was observed in human embryonic lung (HEL) fibroblast cells infected with herpes simplex virus type 1 (HSV-1, wild type or thymidine kinase-deficient) and type 2, or with vaccinia virus (VV). In general, the ethyl substituted compounds (<b>6a–o</b>) had higher antiviral activity and lower cytotoxicity than the methyl substituted analogues (<b>5a–l</b>). The antiviral potency was markedly enhanced by substitution at position 4- of the phenyl ring, with the analogues bearing a 4-methyl (<b>6c</b>), 4-fluoro (<b>6l</b>), or 4-chloro (<b>6n</b>) moiety exhibiting average EC₅₀ values of 1.6 to 6.6 μM against HSV-1, HSV-2, and VV, besides selectivity indices (i.e., ratio of cytotoxic over antiviral concentration) of 21–40. Within the series bearing a substituent at position 3-, the trifluoromethyl analogue <b>6d</b> was unique in suppressing human adenovirus type 2 (AdV-2) and coronavirus HCoV-229E. To conclude, our study highlights the versatility and relevance of the 5-(trifluoromethoxy)-1<i>H</i>-indole-2,3-dione 3-(4-phenylthiosemicarbazones) for developing antiviral agents against different virus families.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146114853","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":"Design, Docking, ADMET, Pass, Synthesis and Bio-Evaluation of Novel 7-O-Substituted Chrysin-Based VEGFR-2 Inhibitors","authors":"Kalyani R. Thombre,&nbsp;Krishna R. Gupta,&nbsp;Milind J. Umekar","doi":"10.1111/cbdd.70250","DOIUrl":"10.1111/cbdd.70250","url":null,"abstract":"<div>\u0000 \u0000 <p>VEGFR-2 is a critical target in cancer therapy, facilitating tumor angiogenesis, yet existing inhibitors face toxicity and resistance issues. Chrysin, a flavonoid with anticancer properties, has VEGFR-2 characteristics but suffers from poor pharmacokinetics. A series of 7-O-substituted chrysin derivatives was designed to improve binding and drug-like properties by integrating key hydrogen-bonding groups and hydrophobic elements, informed by VEGFR-2 structural analysis. To design and assess novel chrysin derivatives through computational predictions and molecular docking; synthesize and characterize selected derivatives; and evaluate their antioxidant and anticancer activities in vitro, to identify effective candidates that exhibit favourable pharmacokinetics and safety. Chrysin derivatives featuring alkylamino and ester substituents were designed using molecular docking against VEGFR-2. ADMET profiling was conducted to anticipate pharmacokinetics and toxicity. In silico cytotoxicity of chrysin and its hybrids was assessed using CLC-Pred 2.0 on the basis of PASS analysis and further analyzed on nine breast cancer cell lines via BC CLC-Pred. Selected derivatives were synthesized via alkylation and esterification and characterized using UV, IR, NMR, and mass spectrometry. Antioxidant activity was evaluated with the DPPH assay, whereas anticancer efficacy against MCF-7 and normal cell lines was measured through cell viability assays, comparing IC₅₀ values to ascorbic acid and sorafenib. Docking studies indicated strong binding affinities, particularly for ester derivatives. ADMET predictions suggested favorable drug-like characteristics. Compound C7 demonstrated remarkable antioxidant activity (IC₅₀ = 0.6 μM), exceeding both chrysin and ascorbic acid. In anticancer tests, C7 and C8 displayed significant cytotoxicity (IC₅₀ = 1.0 and 1.5 μM, respectively), outperforming chrysin and nearing sorafenib efficacy. All other hybrids were found to have moderate inhibitory properties as compared to sorafenib, but better than chrysin. The improved bioactivity and predicted safety of C7 and C8 highlight the efficacy of rational structural modifications in optimizing natural products. Their dual antioxidant and anticancer properties underscore their potential as lead compounds for VEGFR-2-targeted breast cancer treatments. Ester-substituted chrysin derivatives, specifically C7 and C8, demonstrate promising VEGFR-2 inhibition and therapeutic potential, warranting further exploration as multifunctional anticancer agents.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146108985","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":"Pharmacophore-Based Identification and Molecular Characterization of Potent Neprilysin Inhibitors: Biochemical and Therapeutic Implications for Cardiovascular Diseases","authors":"Chung-Ting Kuo,&nbsp;Yi-Chen Wu,&nbsp;Ji-Min Li,&nbsp;Tz-Chuen Ju,&nbsp;Tien-Sheng Tseng","doi":"10.1111/cbdd.70247","DOIUrl":"10.1111/cbdd.70247","url":null,"abstract":"<p>Neprilysin (NEP), a zinc-dependent metalloprotease involved in the degradation of bioactive peptides, represents a validated target for heart failure therapeutics. In this study, a pharmacophore-based virtual screening approach combined with biochemical and biophysical assays, alongside molecular dynamics (MD) simulations, was employed to identify novel NEP inhibitors. The pharmacophore model <b>Phar-A3D2R1</b> successfully identified pentagalloylglucose (PGG) and tannic acid as potent inhibitors, with IC₅₀ values of 17.2 ± 1.5 μM and 10.9 ± 0.7 μM, respectively. Local surface plasmon resonance (LSPR) assays confirmed strong binding affinities (KD = 6.2 ± 0.4 μM for PGG and 5.9 ± 0.5 μM for tannic acid). MD simulations revealed stable ligand–enzyme interactions mediated by hydrogen bonding, hydrophobic contacts, electrostatic interactions, and coordination with the catalytic Zn²⁺ ion. Cytotoxicity assessment in HEK293T cells indicated negligible toxicity. These results validate PGG and tannic acid as promising lead compounds for NEP inhibition and provide a basis for further structure-based optimization toward cardiovascular therapeutics.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70247","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109007","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":"Design, Synthesis and Biological Evaluation of Aminoalkylated Paeonol Chalcone Derivatives","authors":"Jia-chen Xu,&nbsp;Bei-bei Feng,&nbsp;Hong Wu,&nbsp;Li-qin He,&nbsp;Peng Huang","doi":"10.1111/cbdd.70255","DOIUrl":"10.1111/cbdd.70255","url":null,"abstract":"<div>\u0000 \u0000 <p>Twenty-six novel derivatives of paeonol chalcone were synthesized by introducing various hydrophilic aminoalkyl to the 2′-hydroxy of paeonol. Their antiproliferative activity was evaluated by MTT assay against five human cancer cell lines (HeLa, HepG2, U2OS, HCT-116 and A549). The majority of these compounds demonstrated remarkable cytotoxicity against the tested cancer cells. Among them, compound <b>4k</b> exhibited the most potent antiproliferative activity (IC₅₀ values ranging from 1.31 μM to 7.56 μM for the tested cancer cells), stronger than 5-FU (IC₅₀ = 6.29–14.56 μM). Notably, it effectively inhibited the proliferation of HeLa/Taxol cells (IC₅₀ = 14.47 ± 0.02 μM) while showing low cytotoxicity toward normal liver epithelial THLE-2 cells (IC₅₀ = 26.40 ± 0.04 μM). Preliminary mechanistic studies revealed that compound <b>4k</b> induces apoptosis in HeLa cells and downregulates the expression of Cyclin B1 and CDK1, leading to cell cycle arrest at the G2/M transition. Solubility studies revealed that <b>5k</b> (<b>4k</b> hydrochloride) showed excellent aqueous solubility (11.53 mg/mL). SwissADME predictions further supported its potential druggability. Collectively, compound <b>4k</b> represents a promising lead worthy of further investigation as a potential antitumor agent.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095127","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":"Stigmasterol Inhibits Glioma Metastasis and Angiogenesis by Regulating Macrophage Polarization","authors":"Xiangying Li,&nbsp;Danni Huang,&nbsp;Danfeng Wang,&nbsp;Yuan Yuan,&nbsp;Lijie Liu,&nbsp;Haiqing Liu,&nbsp;Qizhou Liang","doi":"10.1111/cbdd.70249","DOIUrl":"10.1111/cbdd.70249","url":null,"abstract":"<div>\u0000 \u0000 <p>Stigmasterol exhibits broad-spectrum anticancer effects, but whether it exerts anti-glioma effects through modulation of macrophage polarization remains unclear. Mouse bone marrow-derived macrophages (BMDMs) were isolated and induced to polarize into M1 and M2 macrophages to obtain conditioned media (CM). GL261 cells were treated with CM and stigmasterol to evaluate their effects on cell function. Murine subcutaneous and metastatic tumor models were established. Cell viability, angiogenesis, migration, and invasion capacities were assessed using Cell Counting Kit-8, tube formation, wound healing, and Transwell assays, respectively. Reverse transcription-quantitative polymerase chain reaction, immunoblotting, immunofluorescence, and immunohistochemical staining were employed to measure mRNA and protein expression levels. Macrophage polarization was analyzed by flow cytometry. The results showed that stigmasterol inhibited glioma growth both in vitro and in vivo and reduced angiogenesis in HUVECs. Moreover, stigmasterol blocked the M2 macrophage-mediated promotion of glioma growth and angiogenesis in HUVECs. The expression of metastasis-related proteins and angiogenic factors in glioma cells induced by M2 macrophages was inhibited by stigmasterol treatment. Furthermore, stigmasterol attenuated macrophage polarization and restrained glioma formation and metastasis in vivo. This study shows that stigmasterol can suppress M2 macrophage polarization to inhibit the progression of gliomas, providing a potential therapeutic compound for glioma treatment.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095082","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":"Estrone-α-2-Deoxy-Glucoside as a Targeted Therapy for Triple-Negative Breast Cancer: Aromatase Inhibition and Cytotoxicity","authors":"Tzu-Yu Huang,&nbsp;Meng-Ru Wang,&nbsp;Feng-Pai Chou,&nbsp;Sheng-Cih Huang,&nbsp;Po-Yun Hsiao,&nbsp;Tung-Kung Wu","doi":"10.1111/cbdd.70251","DOIUrl":"10.1111/cbdd.70251","url":null,"abstract":"<p>Aromatase inhibitors (AIs) are vital in the treatment of estrogen-dependent breast cancer, especially in postmenopausal women. In this study, a series of steroidal glycosides (SGs) derived from <i>trans</i>-androsterone (<i>t</i>AND), estrone (E1), and estradiol (E2) were synthesized using a one-pot multi-enzyme glycosylation approach and structurally characterized via HPLC, MS, and NMR. Among the synthesized compounds, E1-α-2DG (<b>2b</b>) and E2-α-2DG (<b>3b</b>) demonstrated the most potent aromatase inhibition, with IC₅₀ values of 0.101 ± 0.001 μM and 0.159 ± 0.009 μM, respectively. Molecular docking revealed that these glycosides form key hydrogen bonds with catalytic residues and the heme group of CYP19A1. In vitro cytotoxicity showed that E1-α-2DG selectively inhibited the growth of MCF-7 and MDA-MB-231 breast cancer cells in a dose-dependent manner, with the highest potency observed against triple-negative MDA-MB-231 cells (IC₅₀ = 20.46 ± 2.92 μM), while exhibiting no toxicity toward non-cancerous HEK293 cells. These findings suggest that glycosylation enhances the pharmacological potential of steroidal scaffolds and highlights E1-α-2DG as a promising lead compound for the development of safer, dual-function breast cancer therapies.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12857250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146088475","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":"The Immuno-Metabolic Crosstalk in Lung Squamous Cell Carcinoma: Prognostic Insights and Therapeutic Clues","authors":"Haoyuan Xue,&nbsp;Hongwei Li,&nbsp;Songyan Han,&nbsp;Xiaqin Zhang,&nbsp;Tong Liu,&nbsp;Peng Bu,&nbsp;Hua Liang","doi":"10.1111/cbdd.70253","DOIUrl":"10.1111/cbdd.70253","url":null,"abstract":"<div>\u0000 \u0000 <p>Lung squamous cell carcinoma (LUSC) has a poor prognosis due to the lack of effective targeted therapies, and its incidence has increased dramatically in recent years, creating an urgent need for new prognostic markers. Given that tumor immune and metabolic heterogeneity can influence LUSC prognosis, this study aimed to construct a novel predictive model based on immune-related and metabolism-related genes for prognostic stratification in LUSC. Transcriptomic as well as clinical data of 502 and 43 LUSC cases were downloaded from The Cancer Genome Atlas Program (TCGA) and the Gene Expression Omnibus (GEO) databases. Core LUSC subtype genes were identified using nonnegative matrix factorization (NMF), and a prognostic risk model was subsequently constructed by applying machine learning, LASSO regression, and multivariate Cox regression. Based on this model, patients were stratified into low-risk and high-risk subgroups with distinct expression profiles and significant survival differences. Gene-Set Enrichment Analysis of the marker genes revealed that immune pathways were active in the high-risk group, whereas metabolic pathways were prominent in the low-risk group. The two groups also differed in tumor mutation burden and response to clinical therapy. High expression levels of <i>NRTN</i>, <i>CYP2C18</i>, <i>TSLP</i>, <i>MIOX</i>, and <i>RORB</i> and low expression levels of <i>HBEGF</i>, <i>SERPIND1</i>, <i>PTGIS</i>, and <i>LBP</i> were correlated with high survival rates. Immunohistochemical validation in 42 patients confirmed the expression patterns of the identified genetic markers, which were stronger in tumor tissues than in adjacent normal tissues. In conclusion, six immune-related and three metabolism-related genes were identified as prognostic markers of LUSC, with their expression levels significantly associated with the survival rate. The resulting model demonstrates strong predictive power and is expected to help guide treatment strategy decisions.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146136884","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}