Biology Direct最新文献

{"title":"Topological determinants in protein folding dynamics: a comparative analysis of metamorphic proteins.","authors":"Julian Toso, Valeria Pennacchietti, Mariana Di Felice, Eduarda S Ventura, Angelo Toto, Stefano Gianni","doi":"10.1186/s13062-025-00642-x","DOIUrl":"10.1186/s13062-025-00642-x","url":null,"abstract":"<p><p>Protein folding remains a fundamental challenge in molecular biology, particularly in understanding how polypeptide chains transition from denatured states to their functional conformations. Here we analyze the folding mechanisms of the engineered metamorphic proteins B4 and Sb3, which share highly similar sequences but adopt distinct topologies. Kinetic analyses revealed that B4 follows a two-state folding mechanism, whereas Sb3 involves the formation of an intermediate species. We further explore the role of topology in folding commitment using the metamorphic mutant Sb4, which can populate both conformations. By analyzing folding and unfolding behaviors under varying experimental conditions, our findings suggest that topology dictates folding mechanisms at an early stage. These results demonstrate that folding landscapes are primarily shaped by final native structures rather than sequence composition.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"44"},"PeriodicalIF":5.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GAMT facilitates tumor progression via inhibiting p53 in clear cell renal cell carcinoma.","authors":"Bin Zheng, Kan Liu, Ji Feng, Qing Ouyang, Tongyu Jia, Yaohui Wang, Shuo Tian, Xinran Chen, Tianwei Cai, Lequan Wen, Xu Zhang, Xiubin Li, Xin Ma","doi":"10.1186/s13062-025-00641-y","DOIUrl":"10.1186/s13062-025-00641-y","url":null,"abstract":"<p><strong>Background: </strong>Clear cell renal cell carcinoma (ccRCC) is the most common type of RCC. Even though the targeted drugs for the treatment of ccRCC have a certain therapeutic effect, due to the problem of drug resistance, the search for new targets for targeted therapy of ccRCC remains urgent. GAMT is an enzyme involved in creatine metabolism. However, the precise biological roles and molecular mechanisms of GAMT in ccRCC are not fully understood.</p><p><strong>Results: </strong>Here, we found that GAMT was upregulated in ccRCC cells and tissues and associated with poor prognosis. Further, GAMT has pro-oncogenic abilities in promoting ccRCC development and progression. Intriguingly, GAMT exerted biological functions independent of its role in catalyzing creatine synthesis. Mechanistically, GAMT overexpression contributes to the development and progression of ccRCC by inhibiting tumor suppressor p53. Finally, we identified fisetin as a novel GAMT inhibitor and validated its role in suppressing ccRCC progression and sensitizing ccRCC cells to targeted drug axitinib via in vivo and in vitro assays.</p><p><strong>Conclusions: </strong>This study reveals that GAMT has pro-oncogenic abilities in promoting ccRCC development and progression. GAMT exerted its non-enzymatic functions possibly by regulating the expression of p53. Fisetin, the novel GAMT inhibitor identified herein, may serve as a new antitumor drug for ccRCC treatment.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"43"},"PeriodicalIF":5.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic single-cell transcriptomic reveals the cellular heterogeneity and a novel fibroblast subpopulation in laryngotracheal stenosis.","authors":"Ziwei Liao, Yangyang Zheng, Mingjun Zhang, Xiaoyan Li, Jing Wang, Hongming Xu","doi":"10.1186/s13062-025-00639-6","DOIUrl":"10.1186/s13062-025-00639-6","url":null,"abstract":"<p><strong>Background: </strong>Laryngotracheal stenosis (LTS), a pathological narrowing of the upper airway caused by excessive extracellular matrix (ECM) deposition, often leads to dyspnea and even respiratory failure. However, systematic studies addressing the specific subpopulations and their contribution to LTS development still remain underexplored.</p><p><strong>Results: </strong>We collected laryngotracheal tissue at multiple time points of LTS rat model, established by injuring their laryngotracheal lining, and performed dynamic single-cell RNA sequencing (scRNA-seq) to elucidate the transcriptomic atlas of LTS development. The results showed, from the inflammatory state to the repair/fibrotic state, infiltration of immune cells such as monocyte macrophages decreased and fibroblast increased. We delineated the markers and functional status of different fibroblasts subsets and identified that fibrotic fibroblasts may originate from multiple fibroblast subpopulations, including a new subpopulation characterized by the expression of chondrogenic markers such as Ucma and Col2a1, we designated this subcluster as chondrocyte injury-related fibroblasts (CIRF). Furthermore, we categorized monocytes/macrophages into several subtypes and identified that SPP1 high macrophages represented the largest macrophage subpopulation in LTS, providing evidence to clarify the importance of SPP1 macrophages in fibrosis disease. Our findings also revealed the interactions among these cells to explore the molecular mechanism associated with LTS pathogenesis.</p><p><strong>Conclusions: </strong>Our study, for the first time, conducted dynamic scRNA-seq on LTS, revealing the cellular heterogeneity and providing a valuable resource for exploring the intricate molecular landscape of LTS. We propose CIRF may represent a tissue-specific fibroblast lineage in LTS and potentially originate from cells in the perichondrium of the trachea and transform into fibrotic fibroblasts. Integration of our study with those of other respiratory fibrotic diseases will allow for a comprehensive understanding of airway remodeling in respiratory diseases and exploring potential new therapeutic targets for their treatment.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"40"},"PeriodicalIF":5.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the mechanisms of PANoptosis in osteoarthritis and the therapeutic potential of andrographolide through bioinformatics and single-cell analysis.","authors":"Daqian Zhou, Yingjin Luo, Fengjiang Li, Tao Liu, Yongliang Mei, Feilong Li, Xianghan Hou, Zhijiang Fu, Zongchao Liu","doi":"10.1186/s13062-025-00629-8","DOIUrl":"10.1186/s13062-025-00629-8","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA) is a degenerative joint disease marked by the breakdown of cartilage, where apoptosis plays a key role. Although apoptosis-related genes in OA have been studied, a detailed analysis of PANoptosis-related genes and the search for therapeutic drugs remains limited.</p><p><strong>Methods: </strong>We performed a bioinformatics analysis combined with single-cell RNA sequencing to examine PANoptosis-related gene expression in OA cartilage. Key PANoptosis genes and critical cell populations involved in OA progression were identified. Drug prediction led to the selection of Andrographolide (AG), whose effects were validated through molecular docking, Western blotting, and qRT-PCR in chondrocyte models.</p><p><strong>Results: </strong>Several PANoptosis-related genes, including CASP8, TLR3, CASP1, and IL18, were significantly differentially expressed in OA. These genes are linked to processes such as apoptosis, pyroptosis, and the inflammasome complex. Pathway analysis revealed necroptosis, Toll-like receptor, and apoptosis signaling pathways as important in OA pathology. Single-cell analysis identified HomC, EC, and preHTC as key cell populations. AG was predicted to regulate PANoptosis genes, which was confirmed experimentally, demonstrating AG's potential to modulate key genes involved in cartilage degeneration.</p><p><strong>Conclusion: </strong>This study highlights PANoptosis-related genes in OA and identifies Andrographolide as a promising therapeutic drug, offering new insights into OA treatment strategies.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"41"},"PeriodicalIF":5.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the association between osteoporosis and kidney stones: a clinical to mechanistic translational study based on big data and bioinformatics.","authors":"Di Luo, Linguo Xie, Jingdong Zhang, Chunyu Liu","doi":"10.1186/s13062-025-00627-w","DOIUrl":"10.1186/s13062-025-00627-w","url":null,"abstract":"<p><strong>Background: </strong>Osteoporosis and kidney stones share several common pathophysiological risk factors, and their association is well-established. However, previous studies have primarily focused on environmental mediators, such as diet, and the precise mechanism linking these two conditions remains unclear.</p><p><strong>Methods: </strong>The relationship between osteoporosis and kidney stones was analyzed using weighted multivariate logistic regression, employing data from five cycles of the National Health and Nutrition Examination Survey (NHANES) from 2007-2010, 2013-2014, and 2017-2020. Gene expression data from the Gene Expression Omnibus (GEO) microarray database were integrated with machine learning techniques to identify key genes involved in both osteoporosis and kidney stones. Common targets were then identified through the Comparative Toxicogenomics Database (CTD) and GeneCards. GMFA enrichment analysis was performed to identify shared biological pathways. Additionally, drug prediction and molecular docking were employed to further investigate the pharmacological relevance of these targets.</p><p><strong>Results: </strong>Analysis of the NHANES database confirmed a strong association between osteoporosis and kidney stones. Weighted multivariate logistic regression showed that osteoporosis (OR: 1.41; 95% CI 1.11-1.79; P < 0.001) and bone loss (OR: 1.24; 95% CI 1.08-1.43; P < 0.001) were significantly correlated with an increased risk of kidney stones. Three hub genes-WNT1, AKT1, and TNF-were identified through various analytical methods. GMFA revealed that the mTOR signaling pathway is a key shared pathway. Molecular docking studies further confirmed the pharmacological relevance of these targets, demonstrating strong binding affinity between drugs and the proteins involved, consistent with previous findings.</p><p><strong>Conclusion: </strong>Bone loss is associated with an increased risk of kidney stones. Targeting the mTOR signaling pathway may offer a potential therapeutic approach for treating both osteoporosis and kidney stones.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"42"},"PeriodicalIF":5.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The CXCR3/PLC/IP3-IP3R axis is responsible for the ignition of UPR in intestinal epithelial cells exposed to gliadin peptide, during the onset of celiac disease.","authors":"Romina Monzani, Mara Gagliardi, Valentina Saverio, Nausicaa Clemente, Alice Monzani, Ivana Rabbone, Francesca Nigrelli, Samuele Pellizzaro, Emanuele Ferrario, Silvia Saettone, Nico Pagano, Luigina De Leo, Dmitry Lim, Daniele Sblattero, Marco Corazzari","doi":"10.1186/s13062-025-00633-y","DOIUrl":"10.1186/s13062-025-00633-y","url":null,"abstract":"<p><strong>Background: </strong>Coeliac disease is an autoimmune disease that is primarily associated with chronic inflammation of the gut, but can also affect organs outside the gut, from the liver to the skin and CNS. The disease is triggered in predisposed individuals by a peptide mixture (PT) derived from the digestion of gliadin, a component of wheat, which is ingested with food. Although the induction of endoplasmic reticulum stress in intestinal epithelial cells (IECs) upon exposure to PT is known, the underlying molecular mechanisms remain unclear. Identifying the key players in this signaling pathway could therefore help to develop a new effective therapeutic strategy for the treatment of CD patients.</p><p><strong>Methods: </strong>Two CD models were used to identify the molecular mechanism linking extracellular PT and endoplasmic reticulum (ER) stress in the IECs of predisposed individuals exposed to gliadin. These models were an in vitro model based on CaCo-2 cells and an ex vivo model based on our previously described gut ex vivo system (GEVS), both exposed to PT.</p><p><strong>Results: </strong>Our results clearly show that the interaction of gliadin peptides with the transmembrane CXCR3 receptor on IECs leads to a rapid induction of PLC activity that generates IP3 molecules. This second messenger binds to the IP3R located in ER membranes, resulting in calcium efflux from the organelle.</p><p><strong>Conclusion: </strong>The PT-dependent ER stress observed in the IECs of CD patients results from the excessive release of calcium from the ER. Importantly, inhibition of this signaling pathway abrogates ER stress, which in turn attenuates downstream signs of CD, such as TG2 expression and gut permeability dysregulation, as well as inhibits inflammation.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"39"},"PeriodicalIF":5.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of druggable targets in acute kidney injury by proteome- and transcriptome-wide Mendelian randomization and bioinformatics analysis.","authors":"Jiachen Liu, Dianjie Zeng, Yinhuai Wang, Fei Deng, Shuiqing Wu, Zebin Deng","doi":"10.1186/s13062-025-00631-0","DOIUrl":"10.1186/s13062-025-00631-0","url":null,"abstract":"<p><strong>Background: </strong>Acute kidney injury (AKI) remains a critical condition with limited therapeutic options, predominantly managed by renal replacement therapy. The challenge of developing targeted treatments persists.</p><p><strong>Methods: </strong>We integrated genetic data related to druggable proteins and gene expression with AKI genome-wide association study (GWAS) findings. Based on multi-omics Mendelian randomization (MR), we identified the potential causal influence of 5,883 unique proteins and genes on AKI. We also performed using reverse MR and external cohort-based analysis to verify the robustness of this causal relationship. Expression patterns of these targets were examined using bulk transcriptome and single-cell transcriptome data. In addition, drug repurposing analyses were conducted to explore the potential of existing medications. We also constructed a molecular interaction network to explore the interplay between identified targets and known drugs.</p><p><strong>Results: </strong>Genetically predicted levels of seven proteins and twelve genes were associated with an increased risk of AKI. Of these, six targets (NCF1, TNFRSF1B, APEH, ACADSB, ADD1, and FAM3B) were prioritized based on robust evidence and validated in independent cohorts. Reverse MR showed a one-way causal relationship of targets. These targets are predominantly expressed in proximal tubular cells, endothelial cells, collecting duct-principal cells, and immune cells within both AKI-affected and normal tissues. Several promising drug repurposing opportunities were identified, such as telmisartan-NCF1, calcitriol-ACADSB, and ethinyl estradiol-ACADSB. The molecular interaction mapping and pathway integration analysis provided further insights, suggesting potential strategies for combinatorial therapies.</p><p><strong>Conclusions: </strong>This extensive investigation identified several promising therapeutic targets for AKI and highlighted opportunities for drug repurposing. These findings offer valuable insights that could shape future research and the development of targeted treatments.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"38"},"PeriodicalIF":5.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"c-Jun promotes neuroblastoma cell differentiation by inhibiting APC formation via CDC16 and reduces neuroblastoma malignancy.","authors":"Yunyun Wang, Jingjing Huang, Zhenhua Song, Shuo Zhang, Haojie Guo, Qi Leng, Na Fang, Shaoping Ji, Jian Yang","doi":"10.1186/s13062-025-00630-1","DOIUrl":"10.1186/s13062-025-00630-1","url":null,"abstract":"<p><p>Neuroblastoma is a pediatric embryonal malignancy characterized by impaired neuronal differentiation. Differentiation status in neuroblastoma strongly affects the clinical outcome, thus, enforcement of differentiation becomes a treatment strategy for this disease. However, the molecular mechanisms that control neuroblastoma differentiation are poorly understood. As an extensively studied protein of the activator protein-1 (AP-1) complex, c-Jun is involved in numerous cell regulations such as proliferation, survival and differentiation. In the current study, we demonstrated that c-Jun expression was upregulated by retinoic acid (RA) and flow cytometry assay indicated c-Jun overexpression arrested cell cycle to G1 phase, which, in turn, promoted the initiation of neuroblastoma cell differentiation. Co-immunoprecipitation (co-IP) assay showed that c-Jun competitively interacted with CDC16, a key subunit in anaphase-promoting complex (APC), resulting in reduced APC formation and inhibition of cell cycle progression. Furthermore, EdU proliferation assay and transwell experiment showed that c-Jun overexpression inhibited neuroblastoma cell proliferation and migration via interacting and sequestering CDC16. These findings identify c-Jun as a key regulator of neuroblastoma cell cycle and differentiation and may represent a promising therapeutic target to induce neuroblastoma differentiation via the interaction between c-Jun and CDC16.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"37"},"PeriodicalIF":5.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating extracellular vesicles regulate ELAVL1 by delivering miR-133a-3p which affecting NLRP3 mRNA stability inhibiting PANoptosome formation.","authors":"Deliang Wang, Zheng Dai, Lu Jiang, Ke Liu","doi":"10.1186/s13062-025-00605-2","DOIUrl":"10.1186/s13062-025-00605-2","url":null,"abstract":"<p><strong>Background: </strong>In the quest to elucidate novel therapeutic strategies for myocardial injury, recent investigations have underscored the pivotal roles played by circulating extracellular vesicles (EVs) in intercellular communication.</p><p><strong>Method: </strong>EVs were extracted from individuals who had experienced AMI-EVs and those who were N-EVs. To assess the impact of circulating EVs on cardiomyocyte and endothelial cell proliferation, apoptosis, migration, and tube formation, a range of in vitro assays such as CCK8, EdU assays, flow cytometry, wound healing assays and angiogenesis assays were conducted. Differentially expressed miRNAs in EVs were validated using microarray analysis and real-time PCR. Through bioinformatics analysis, ELAVL1 was identified as a potential downstream target of miR-133a-3p. This finding was further confirmed by conducting dual-luciferase reporter assay and RNA co-immunoprecipitation experiments. To investigate the regulatory effects of circulating EVs from various sources on myocardial injury and PANoptosis, an animal model of ischemia-reperfusion-induced myocardial injury was established.</p><p><strong>Result: </strong>Our findings revealed that circulating EVs effectively deliver miR-133a-3p to target cells, where it binds to ELAVL1, leading to a decrease in NLRP3 mRNA stability. This reduction in NLRP3 mRNA stability subsequently inhibits the assembly of the PANoptosome, a multi-protein complex implicated in PANoptosis. As a result, we observed a significant mitigation of PANoptosis in our myocardial injury models, demonstrating the protective role of miR-133a-3p against excessive cell death.</p><p><strong>Conclusion: </strong>The present study underscores the regulatory role of circulating EV-delivered miR-133a-3p in modulating PANoptosis through ELAVL1-mediated NLRP3 mRNA stabilization. This mechanism represents a potential therapeutic target for attenuating myocardial injury by suppressing PANoptosis.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"36"},"PeriodicalIF":5.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic and immunological implications of protein kinases in gastric cancer: a focus on hub gene ABL2 and its impact on the polarization of M2 macrophages.","authors":"Di Chen, Ju Huang, Aiming Yang, Zhifan Xiong","doi":"10.1186/s13062-025-00636-9","DOIUrl":"10.1186/s13062-025-00636-9","url":null,"abstract":"<p><strong>Background: </strong>Protein kinases are essential cellular signal modulators involved in tumorigenesis, metastasis, immune response, and drug resistance. However, the comprehensive features and clinical significance of protein kinases in gastric cancer (GC) remain inconclusive.</p><p><strong>Methods: </strong>We analyzed the transcriptional profiles of protein kinases in GC patients from the GEO and TCGA databases. Based on differentially expressed kinase genes (DE-KGs), a novel cluster was identified to assess its association with patient survival and the tumor microenvironment (TME) in GC. Subsequently, an optimal DE-KGs-based model (DE-KGsM) was determined using 101 machine-learning algorithm combinations. This model was evaluated using multi-omics data to investigate its associations with patient prognosis, clinical features, tumor microenvironment, tumor-infiltrating immune cells (TIICs), and immunotherapy response. Furthermore, scRNA-seq analysis and TIMER algorithm were applied to determine the correlation between the hub gene (ABL2) in the DE-KGsM and Macrophages. Finally, in vitro experiments were performed to explore the immune-related mechanisms of ABL2 in GC.</p><p><strong>Results: </strong>We identified two molecular subtypes of GC patients based on 64 DE-KGs expression. Significant differences were observed in overall survival and TIIC characteristics between Cluster 1 and Cluster 2. Among these 64 DE-KGs, we identified an optimal DE-KGsM that could be a prognostic indicator in GC. TIICs and TIDE analyses exhibited that GC patients in the high-DE-KGsM score group had a higher proportion of M2 macrophages and lower response rates to ICI treatment. scRNA-seq analysis indicated that ABL2 might play an indispensable role in tumor immunity. Furthermore, in vitro experiments demonstrated that ABL2 accelerated the proliferation, migration, and invasion of GC cells, as well as the polarization of M2 macrophages.</p><p><strong>Conclusions: </strong>The DE-KGsM could be a powerful predictor of GC patients' survival and might facilitate the development of personalized therapy. Furthermore, as a hub gene in the DE-KGsM, ABL2 could be an immunological biomarker that modulates the polarization of M2 macrophages, thereby promoting GC progression.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"35"},"PeriodicalIF":5.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}