Chemical biology & drug design最新文献

{"title":"Network Pharmacology, Machine Learning, Molecular Docking, and Cell Experiments Reveal the Therapeutic Mechanism of Radix Rehmanniae Praeparata in Psoriasis In Vitro.","authors":"Tingting Zhang, Liping Wei, Haoen Liu, Bin Zhou","doi":"10.1111/cbdd.70309","DOIUrl":"10.1111/cbdd.70309","url":null,"abstract":"<p><p>Psoriasis is an immune-mediated chronic inflammatory skin disease. Radix Rehmanniae Praeparata (RRP) is a traditional Chinese medicine with abundant biological functions. This study was performed to analyze the potential functional mechanism of RRP using network pharmacology, machine learning, molecular docking, and cell experiments. Active ingredients of RRP were screened from the TCMSP database, and targets were obtained from TCMSP and Swiss Target Prediction. Targets of psoriasis were acquired from GSE274560, GeneCards, and CTD. The protein-protein interaction network was analyzed by the String website. KEGG, Reactome, and GO were analyzed to predict possible pathways. LASSO and SVM-RFE machine learning algorithms were used to screen significant targets. Interaction between active ingredients and core targets was validated by molecular docking and molecular dynamics simulation. In vitro cell experiments were conducted using human keratinocytes HaCaT, including CCK-8, Western blotting, EdU, and ELISA. Sitosterol and Stigmasterol acted as the active ingredients of RRP. A total of 145 targets for the two ingredients were screened, and 18,871 targets were obtained for psoriasis. Furthermore, 27 intersection targets were considered as the candidate target genes of RRP for psoriasis treatment. LASSO and SVM-RFE identified RORC and HSD11B1 as core targets. Molecular docking showed the binding between Sitosterol or Stigmasterol and RORC or HSD11B1. Molecular dynamics simulation further validated the binding between Stigmasterol and RORC or HSD11B1. Cell experiments indicated that Stigmasterol inhibited HaCaT proliferation and inflammation via inducing HSD11B1 upregulation. These findings demonstrate that the mechanism of RRP in psoriasis is multi-target and multi-pathway. This study has unraveled the preliminary mechanism of RRP in treating psoriasis, which involves Stigmasterol-mediated HSD11B1 upregulation.</p>","PeriodicalId":93931,"journal":{"name":"Chemical biology & drug design","volume":"107 5","pages":"e70309"},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147936346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the Elongin BC-BC-Box Interface: Structural Insights, Peptidic Disruptors and Emerging Small-Molecule Strategies.","authors":"Emadeldin M Kamel, Sally Mostafa Khadrawy, Ahmed A Allam, Noha A Ahmed, Faris F Aba Alkhayl, Al Mokhtar Lamsabhi","doi":"10.1111/cbdd.70307","DOIUrl":"10.1111/cbdd.70307","url":null,"abstract":"<p><p>Protein-protein interactions (PPIs) that orchestrate ubiquitin-dependent signaling have long challenged drug discovery because their interfaces are typically large and hydrophobic. The heterodimeric adaptor Elongin BC (ELOB/ELOC) defies this stereotype: its BC-box-binding groove is a deep, rigid pocket that anchors dozens of cellular and viral partners to cullin-RING ligases and to transcriptional machinery. Recent structural and chemical-biology breakthroughs have converted this once \"undruggable\" site into a tractable target. A sub-nanomolar peptide derived from the chromatin factor EPOP has been shown to displace native BC-box proteins, trigger apoptosis in multiple cancer lines, and unveil a transcriptomic signature that converges on MYC and cell-cycle control. Parallel fragment screens and crystallography have mapped adjacent hot spots suitable for small-molecule growth, while functional genomics highlights Elongin BC as a pan-cancer dependency and an unexpected regulator of the SARS-CoV-2 co-receptor TMPRSS2. This review synthesizes the structural principles of BC-box recognition, the current state of peptide and fragment-based inhibitors, and the biological consequences of disrupting the Elongin BC hub. We discuss therapeutic prospects in oncology and virology, outline key challenges-delivery, selectivity, and resistance-and propose future directions ranging from stapled-peptide optimization to covalent fragment tethering and PROTAC strategies. Together, these advances position Elongin BC inhibition at the forefront of next-generation PPI drug discovery, offering a unified approach to modulate ubiquitin signaling, epigenetic regulation, and viral entry through a single conserved pocket.</p>","PeriodicalId":93931,"journal":{"name":"Chemical biology & drug design","volume":"107 5","pages":"e70307"},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Binding Mode Based Chemical Screening Method Utilizing D-Ala-D-Ala Silica Gel Facilitating the Discovery of Overlooked Binding Affinity and Antibacterial Activity.","authors":"Aoi Kimishima, Rina Suzuki, Sota Honma, Shohei Kosaka, Paul Wasuwanich, Yuki Suzuki, Hidehito Matsui, Hideaki Hanaki, Taichi Kamo, Yukiko Ujie, Takuji Nakashima, Yukihiro Asami","doi":"10.1111/cbdd.70305","DOIUrl":"10.1111/cbdd.70305","url":null,"abstract":"<p><p>In this work, a new chemical screening method has been established, namely binding mode-based chemical screening (BMBC), using D-Ala-D-Ala-functionalized silica gel. This method was inspired by the binding mode of vancomycin to the bacterial cell wall and enables the discovery of new natural compounds with antibacterial activity. In this study, we aimed to uncover overlooked binding affinity and antibacterial activity of compounds from our in-house natural product library (the Ōmura Natural Compound Library) and estimated the binding constants of hit compounds to empower BMBC method to show the utility and validity. Ultimately, we discovered the overlooked binding affinity and antibacteria activity of ascofuranone and cercosporin. Particularly, cercosporin demonstrated remarkable antibacterial activity against Staphylococcus epidermidis clinical isolates.</p>","PeriodicalId":93931,"journal":{"name":"Chemical biology & drug design","volume":"107 5","pages":"e70305"},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prunetin Protects Against Sepsis-Induced Acute Lung Injury by Inhibiting Inflammation and Oxidative Stress via Regulating the TLR4/NF-κB/NLRP3 Inflammasome Pathway.","authors":"Xuedong Zhang, Siqi Dai, Chaojie Li, Tu Shen, Fengxiang Zhang","doi":"10.1111/cbdd.70301","DOIUrl":"10.1111/cbdd.70301","url":null,"abstract":"<p><p>Prunetin is a naturally occurring flavonoid with effective therapeutic potential against diverse diseases. This study aimed to investigate the potential properties of prunetin in alleviating lipopolysaccharide (LPS)-induced inflammatory responses and oxidative stress in an acute lung injury (ALI) mouse model and murine alveolar macrophages (MH-S cells). The results showed that prunetin protected against LPS-induced ALI in mice, as shown by improved histopathological alterations in lung tissues, reduced lung injury score, and decreased lung wet/dry weight ratio. Furthermore, prunetin attenuated LPS-induced inflammatory responses and oxidative stress both in vivo and in vitro. Prunetin treatment attenuated LPS-induced increase in the expression of toll-like receptor 4 (TLR4), phosphorylated nuclear factor kappa B (NF-κB) p65, nuclear p65, NLR family pyrin domain containing 3 (NLRP3), and ASC, implying that prunetin inhibited LPS-induced activation of the TLR4/NF-κB/NLRP3 inflammasome pathway. Moreover, TLR4 overexpression abolished the inhibitory effects of prunetin on LPS-induced inflammatory responses and oxidative stress in MH-S cells. In summary, our results suggested that prunetin protected against LPS-induced ALI through inhibiting inflammation and oxidative stress via regulating the TLR4/NF-κB/NLRP3 inflammasome pathway. These results support that prunetin may serve as a promising agent for the treatment of sepsis-related ALI.</p>","PeriodicalId":93931,"journal":{"name":"Chemical biology & drug design","volume":"107 4","pages":"e70301"},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147792170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyrazoline-Imidazopyridine Hybrids as Beclin-1 Mimetics Driving Dual Apoptotic and Autophagy in Breast Cancer.","authors":"Rashmi Shivakumar, Narasimha M Beeraka, Riyaz Ali M Osmani, Bhoomika B Ravi, Monisha H S Yadhav, Dileep Nagaraju, Chandra Sekhar Bhol, Allaka Nagalakshmi, Kwang Seok Ahn, Vladimir N Nikolenko, Arunachalam Chinnathambi, Andreas Bender, Basappa Basappa","doi":"10.1111/cbdd.70287","DOIUrl":"10.1111/cbdd.70287","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Breast cancer is a profound cause of mortality among women globally. Similar to BH3 mimetics, targeting the antiapoptotic Bcl-xL:Beclin1 protein complex is crucial to inducing apoptosis and autophagy, thereby suppressing tumor progression in breast cancer cells. This study aims to synthesize and evaluate a series of imidazopyridine-tethered pyrazoline drug prejudice-scaffold derivatives (5a-5l) as Beclin-1 mimetics that induce apoptosis and autophagy and mainly for their potential anticancer activity, focusing on the most potent compound 5c. The primary goal is to assess its ability of compound 5c to inhibit Bcl-xL:Beclin-1 interaction, thereby inducing a protective autophagic response subsequently to assess apoptosis to suppress breast cancer cell proliferation. Molecular docking studies were conducted to evaluate the binding affinity of compound 5c with Bcl-xL, and the interactions were visualized through a three-dimensional interaction map, highlighting key stabilizing interactions. Cytotoxic effects of compound 5c on MCF-7 breast cancer cells were assessed using alamarblue assay. To investigate the antiproliferative potential, colony formation, and wound healing assays were performed at varying concentrations. Apoptotic induction was analyzed through Western blotting for key proteins (BAX, Bcl-xL, Bcl-2), caspase-3/7 activation, and AnnexinV/PI assay using flow cytometry. Additionally, autophagy was examined by monitoring LC3B-I to LC3B-II conversion, Beclin-1 upregulation, and lysosomal activity using LysoTrackerRed staining. The involvement of compound 5c in autophagic flux was further confirmed by quantifying LC3-II accumulation in the presence of an autophagy inhibitor chloroquine (CQ), and then the effect of 5c-induced cell viability and apoptosis were evaluated and caspase-3/7 activity, respectively, during autophagy inhibition condition in MCF-7 cell line. A strong binding interaction of compound 5c with the hydrophobic groove of Bcl-xL demonstrated its potential as an effective Bcl-xL inhibitor. Compound 5c significantly reduced MCF-7 cell viability in a dose-dependent manner (IC50: 9.7 μM). The inhibitory effect of compound 5c on cancer cell proliferation and migration was observed. Treatment with compound 5c induced dose-dependent apoptosis in MCF-7 cells, as confirmed by Annexin V/PI using flow cytometric analysis after 72 h of exposure. A significant decrease in viable cells accompanied by an increase in apoptotic cell populations was observed with increasing concentrations of 5c. Upregulated BAX expression and downregulation in Bcl-xL and Bcl-2 expression levels indicated apoptosis induction. Caspase-3/7 activation further confirmed apoptotic cell death. Autophagy assessment revealed enhanced LC3B-II accumulation, Beclin-1 upregulation, and reduced p62 levels, suggesting modulation of autophagy. CQ treatment further increased LC3-II levels, indicating compound 5c-mediated autophagic flux induction and a significant reductio","PeriodicalId":93931,"journal":{"name":"Chemical biology & drug design","volume":"107 4","pages":"e70287"},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147701138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preliminary Study on the Mechanism of Arctigenin in Alleviating Osteoarthritis Pain by Suppressing Chondrocyte Pyroptosis: The Potential Role of the POU2F1/GRB10 Axis.","authors":"Tian-Jun Zhai, Wei Feng, Cheng-Cheng Zhu, Ye-Ping Chen, Hui Zhang","doi":"10.1111/cbdd.70300","DOIUrl":"10.1111/cbdd.70300","url":null,"abstract":"<p><p>Osteoarthritis (OA), the most prevalent form of arthritis globally, is characterized by debilitating pain driven by inflammatory and degenerative processes in chondrocytes. Here, we demonstrate that arctigenin (ATG), a bioactive lignan from Arctium lappa, alleviates OA pain by suppressing chondrocyte pyroptosis through the POU Class 2 Homeobox 1 (POU2F1)/growth factor receptor Bound Protein 10 (GRB10) signaling axis. In a monosodium iodoacetate (MIA)-induced OA rat model, ATG administration reduced pain hypersensitivity, lowered pro-inflammatory cytokines, and elevated anti-inflammatory interleukin-10 (IL-10), while diminishing expression of pyroptosis effectors including cleaved caspase-1, Gasdermin-D-N (GSDMD-N), and NOD-like receptor thermal protein domain associated protein 3 (NLRP3). In vitro studies in C28/I2 chondrocytes revealed that ATG dose-dependently attenuated inflammation and pyroptosis markers. Mechanistically, ATG upregulated POU2F1, a transcription factor that directly binds and activates the GRB10 promoter, as confirmed by enrichment and binding assays. Silencing POU2F1 or GRB10 reversed ATG's inhibitory effects on pyroptosis. In vivo validation further showed that ATG's pain-relieving effects in OA rats depend on this axis to curb chondrocyte pyroptosis. Collectively, these findings highlight ATG's potential as a novel analgesic agent for OA by targeting pyroptotic pathways, offering insights into inflammation-driven pain mechanisms.</p>","PeriodicalId":93931,"journal":{"name":"Chemical biology & drug design","volume":"107 4","pages":"e70300"},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147792237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Hemisynthesis, Computational, and Biological Evaluation of Novel Totarol-1,3-Thiazol Derivatives as Anticancer Agents.","authors":"Ayoub Boualli, Mourad Fawzi, Yassine Laamari, Lubna Tahtamouni, Sultan Erkan, Abdelkhalek Riahi, Anthony Robert, My Youssef Ait Itto, Aziz Auhmani","doi":"10.1111/cbdd.70288","DOIUrl":"10.1111/cbdd.70288","url":null,"abstract":"<p><p>The current study reports the design and synthesis of novel totarol-based 1,3-thiazole derivatives DBT2-9 and evaluates their anticancer potential. The synthesis involved the reaction of totarol derivatives with thiosemicarbazone derivatives under optimized conditions. Structural characterization of the synthesized compounds was accomplished using high-resolution mass spectrometry (HRMS), infrared spectroscopy (IR), and nuclear magnetic resonance (NMR) spectroscopy, confirming their chemical identities and purity. The antitumor activity of these compounds was evaluated using the in vitro MTT and apoptosis assays. The compounds demonstrated selective anti-proliferative effects against MCF-7 breast cancer cells, and compound DBT9 had an IC₅₀ value comparable to those of reference anticancer drugs. By activating caspases 4 and 8, which mediate the stress-mediated and extrinsic apoptosis pathways, respectively, compound DBT9 caused MCF-7 cell death. Furthermore, density functional theory (DFT) was carried out to study the electronic properties and the chemical reactivity of the synthesized compounds. Furthermore, molecular docking studies revealed that DBT9 displayed the highest binding affinity toward multiple cancer-associated target proteins, including EGFR, VEGFR-2, and FGFR1. These findings indicate that DBT9 showed the best cytotoxic activity through the induction of apoptosis via caspase 4 and 8 pathways, indicating its potential as a promising bioactive compound.</p>","PeriodicalId":93931,"journal":{"name":"Chemical biology & drug design","volume":"107 4","pages":"e70288"},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147679538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bruceine A Suppresses Triple-Negative Breast Cancer Growth and Metastasis by Inducing GPX4-Dependent Ferroptosis via Ubiquitin-Proteasome-Mediated Degradation.","authors":"Hengguan Cui, Xinyu Liu, Weixing Shen, Ping Zhang","doi":"10.1111/cbdd.70293","DOIUrl":"10.1111/cbdd.70293","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited targeted therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising strategy for treating refractory cancers. Here, we identify Bruceine A (BA), a natural quassinoid, as a potent inducer of GPX4-dependent ferroptosis in TNBC. BA suppressed proliferation, clonogenic survival, migration, and invasion of MDA-MB-231 and 4T1 cells and significantly reduced tumor growth and pulmonary metastasis in vivo. Mechanistically, BA induced iron accumulation, lipid peroxidation, and oxidative stress, consistent with ferroptotic activation. Genetic ablation of GPX4 resulted in elevated basal ferroptotic stress and abolished further BA-induced lipid peroxidation and ferroptotic amplification, indicating that BA-mediated ferroptosis requires functional GPX4. At the molecular level, BA reduced GPX4 expression at both transcriptional and post-translational levels. BA accelerated GPX4 protein turnover through ubiquitin-proteasome-mediated degradation, accompanied by enhanced ubiquitination. Molecular docking and dynamics simulations supported a stable interaction between BA and GPX4, providing structural insight into its destabilization. Collectively, these findings establish BA as a GPX4-dependent ferroptosis inducer that suppresses TNBC growth and metastasis, highlighting targeting of GPX4 stability as a potential therapeutic strategy in TNBC.</p>","PeriodicalId":93931,"journal":{"name":"Chemical biology & drug design","volume":"107 4","pages":"e70293"},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147679496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Virtual Screening and Molecular Dynamics Simulation Study to Discover Potential Activators of γ-Aminobutyric Acid B Receptor 1 for Therapeutic Targeting of Neurodegenerative Diseases.","authors":"Asfiya, Sneh Prabha, Arunabh Choudhury, Abdelbaset Mohamed Elasbali, Afzal Hussain, Mohamed F Alajmi, Md Imtaiyaz Hassan","doi":"10.1111/cbdd.70294","DOIUrl":"10.1111/cbdd.70294","url":null,"abstract":"<p><p>Neurodegenerative disorders are characterized by imbalances in synaptic signaling, often driven by dysregulation of the γ-aminobutyric acid B receptor 1 (GABBR1). Its dysregulation has been identified as a key pathophysiological mechanism contributing to the synaptic failure and neural network instability observed in major neurodegenerative disorders. Therapeutic strategies that target GABBR1 activation offer a promising approach to restoring excitatory-inhibitory homeostasis in the central nervous system. This study employed an integrated computational workflow to identify potent GABBR1 modulators by repurposing an FDA-approved drug library. Structure-based virtual screening, PASS analysis, and binding site interaction analysis identified Cinacalcet and Trifluperidol as top candidates, exhibiting binding affinities of -10.2 and -9.0 kcal/mol, respectively, which are higher than that of the reference antagonist (-6.0 kcal/mol). Density functional theory calculations confirmed the favorable electronic properties and reactivity for both compounds. The molecular dynamics (MD) simulations of 500 ns validated the structural stability of GBARR1-ligand complexes, revealing that Cinacalcet induces a compact, rigid GABBR1 conformation. MM/PBSA analysis demonstrated robust binding free energies of -21.50 kcal/mol for Cinacalcet and -13.13 kcal/mol for Trifluperidol. These findings suggest that Cinacalcet and Trifluperidol are promising candidates for drug repurposing in the treatment of neurodegenerative diseases caused by the dysregulation of GABBR1. This study contributes to public health research and aligns with Sustainable Development Goal 3 (Good Health and Well-being) by supporting the development of novel therapeutic strategies for neurodegenerative diseases.</p>","PeriodicalId":93931,"journal":{"name":"Chemical biology & drug design","volume":"107 4","pages":"e70294"},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147679461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemoresistance and Immune Suppression in Gastric Cancer Are Driven by PPDPF Overexpression.","authors":"Chenqiang Pan, Rongxing Hu, Bing Wu, Lei Tan, Zhiqiang Yan","doi":"10.1111/cbdd.70299","DOIUrl":"10.1111/cbdd.70299","url":null,"abstract":"<p><p>Gastric cancer (GC) remains a lethal malignancy, and there is a pressing need for novel therapeutic targets. This study aimed to identify key oncogenic drivers in GC. Through integrative bioinformatic analysis of TCGA and GEO transcriptomic datasets, coupled with single-cell sequencing data, we identified PPDPF as a candidate gene that is specifically enriched in malignant gastric epithelial cells and associated with poor prognosis. Functional in vitro assays confirmed that PPDPF overexpression significantly enhanced the viability, migration, and invasion of GC cell lines. Mechanistically, RNA sequencing revealed that PPDPF broadly suppresses antitumor immunity, notably by downregulating key ligands of the CXCR3 axis and correlating with specific immune checkpoint profiles. Furthermore, bioinformatic predictions combined with experimental validation (RT-PCR, ELISA, and drug sensitivity assays) demonstrated that high PPDPF expression fosters an immunosuppressive tumor microenvironment and confers resistance to 5-Fluorouracil and Oxaliplatin. In conclusion, this study is the first to establish PPDPF as a critical molecular driver that promotes malignant progression, orchestrates an immunosuppressive microenvironment, and mediates chemotherapy resistance in gastric cancer. Our findings position PPDPF as a potential novel prognostic biomarker and therapeutic target, providing a theoretical foundation for developing personalized treatment strategies for patients with gastric cancer.</p>","PeriodicalId":93931,"journal":{"name":"Chemical biology & drug design","volume":"107 4","pages":"e70299"},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147694051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}