Biology Direct最新文献

{"title":"Structural and functional insights into Ubl domain-mediated regulation of SARS-CoV-2 PLpro.","authors":"Rimanshee Arya, Janani Ganesh, Vishal Prashar, Mukesh Kumar","doi":"10.1186/s13062-025-00690-3","DOIUrl":"10.1186/s13062-025-00690-3","url":null,"abstract":"<p><strong>Background: </strong>SARS-CoV-2 papain-like protease (PLpro) is essential for viral replication and immune evasion. It contains an N-terminal ubiquitin-like (Ubl) domain, whose involvement in enzymatic function remains poorly understood.</p><p><strong>Results: </strong>In this study, we investigated the role of the Ubl domain in modulating the structural dynamics and catalytic efficiency of PLpro. Using molecular dynamics (MD) simulations, inhibitor binding assays, and steady-state kinetic analyses, we found that the Ubl domain stabilizes critical structural elements, notably the ridge helix in the thumb subdomain. Removal of the Ubl domain altered substrate processing, reducing catalytic efficiency of the enzyme. Interestingly, free ubiquitin enhanced enzymatic activity, likely via non-canonical binding sites distinct from the SUb1 and SUb2 sites.</p><p><strong>Conclusion: </strong>These findings uncover a regulatory role for the Ubl domain in allosteric modulation of PLpro activity and reveal additional layers of enzymatic plasticity. Understanding these mechanisms could guide the design of future antiviral therapeutics targeting PLpro's regulatory or allosteric sites.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"102"},"PeriodicalIF":4.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225037","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":"HMGA1 promotes the progression of lung adenocarcinoma through the STAT1-mediated transcriptional activation of DDAH1.","authors":"Tong Hu, Run Shi, Shiyuan Yin, Tingting Xu, Yangyue Xu, Duo Xu, Yongqian Shu","doi":"10.1186/s13062-025-00688-x","DOIUrl":"10.1186/s13062-025-00688-x","url":null,"abstract":"<p><strong>Background: </strong>Advancements in precision oncology have generated increased interest in the prognostic and therapeutic capabilities of transcription factors, among which HMGA1 is significantly correlated with LUAD prognosis. However, our understanding of HMGA1 remains insufficient. This study seeks to elucidate the biological functions of HMGA1 and to investigate the underlying mechanisms.</p><p><strong>Methods: </strong>The prognostic value of HMGA1 was validated across multiple independent patient cohorts with LUAD, and its impact on tumor proliferation was verified by both in vitro and in vivo models. A series of experiments were performed to investigate the underlying molecular mechanism, including RNA sequencing, co-immunoprecipitation and chromatin immunoprecipitation.</p><p><strong>Results: </strong>HMGA1 plays a crucial role in promoting the proliferation of LUAD. The underlying mechanism involves the recruitment of STAT1 to the promoter region of DDAH1, which synergistically increases its transcription and subsequently activates the ADMA/NO signaling pathway. Notably, the STAT1 inhibitor fludarabine has been shown to effectively impede the progression of LUAD models characterized by high levels of HMGA1.</p><p><strong>Conclusion: </strong>Our research reveals a previously unrecognized mechanism through which the HMGA1/STAT1 complex facilitates LUAD proliferation by transcriptionally activating DDAH1. Moreover, we propose that fludarabine could serve as a promising therapeutic option for LUAD patients exhibiting elevated levels of HMGA1.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"101"},"PeriodicalIF":4.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205400","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":"MINPP1 promotes ferroptosis in HBV-related hepatocellular carcinoma by regulating CTSB K33-linked deubiquitination via ZRANB1.","authors":"Wenbiao Chen, Yang Song, Liyang Wang, Feng Xiong, Shenggang Zhang","doi":"10.1186/s13062-025-00686-z","DOIUrl":"10.1186/s13062-025-00686-z","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is significantly influenced by hepatitis B virus (HBV) infection. However, the roles of ferroptosis and ubiquitination modifications in this context remain poorly understood.</p><p><strong>Methods: </strong>In this study, we utilized immunoprecipitation, immunofluorescence, and analysis of ubiquitin modifications to explore the regulatory mechanisms of MINPP1 in ferroptosis and its effects on tumor progression. Further mechanistic studies revealed that ZRANB1 regulates the K33-linked ubiquitination of CTSB. Ultimately, the contribution of the MINPP1-CTSB axis to tumor progression was validated using in vivo experiments.</p><p><strong>Results: </strong>Our study demonstrates that MINPP1 regulates ferroptosis in HBV-positive HCC cells via a glycolytic bypass mechanism. Bioinformatics analysis indicates that MINPP1 stabilizes CTSB, thereby participating in the regulation of ferroptosis. Specifically, MINPP1 modulates K33-linked deubiquitination of CTSB through ZRANB1, which stabilizes CTSB expression and identifies its deubiquitination site. In contrast, the MINPP1-ZRANB1-CTSB axis does not regulate ferroptosis in HBV-negative HCC cells. However, upon the introduction of HBV into these cells, the MINPP1-ZRANB1-CTSB axis becomes active and promotes ferroptosis. Finally, in vivo assays showed that MINPP1 regulates tumor progression by regulating K33-linked ubiquitination of CTSB, thereby affecting ferroptosis levels.</p><p><strong>Conclusion: </strong>Our research showed outcomes suggest that the MINPP1-ZRANB1-CTSB axis promotes ferroptosis in HBV-positive HCC cells through glycolysis, emphasizing the function of MINPP1 in mediating ferroptosis in HBV-related HCC cells via CTSB deubiquitination modification. This provides valuable insights and a foundation for the treatment of HBV-associated HCC.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"100"},"PeriodicalIF":4.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205416","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":"Phage-encoded protein PavP modulates Pseudomonas aeruginosa virulence by dual inhibition of growth and pathogenic traits.","authors":"Yiming Yang, Wenbo Yan, Yuanli Zhao, Tingting Gao, Yingxin Yang, Linke Cao, Ruixue Tao, Na Liu, Yunlei Yang, Yanrong Liu, Meng Li, Lijun Liu, Yani Zhang, Tietao Wang","doi":"10.1186/s13062-025-00689-w","DOIUrl":"10.1186/s13062-025-00689-w","url":null,"abstract":"<p><p>Pseudomonas aeruginosa, one of the most prevalent pathogens, is notorious for its multidrug resistance, necessitating novel therapeutic strategies. Phage therapy has emerged as a promising alternative treatment strategy, which offers a dual advantage by directly killing bacteria and modulating host-pathogen interactions. Here, we identify PavP (PaoP5_160), a small protein encoded by bacteriophage PaoP5, which exhibits bacteriostatic activity on P. aeruginosa while altering virulence pathways at sub-inhibitory concentrations. Specifically, PavP impairs bacterial motility, enhances biofilm formation, and upregulates type 3 secretion system expression. The global transcriptome analysis shows that PavP modulates multiple pathways which participate in the pathogenicity and cell vitality of host bacteria. Crucially, in vivo virulence assays confirm that PavP attenuates P. aeruginosa pathogenicity. Our results reveal PavP as a multifunctional virulence modulator in P. aeruginosa, which highlights its potential as a dual-target antimicrobial agent capable of simultaneously restricting bacterial proliferation and disrupting virulence networks.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"99"},"PeriodicalIF":4.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198302","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":"Necroptosis-driven T cell activation promotes IL-6-mediated PD-L1 upregulation in cholangiocarcinoma cells: IL-6 gene signature as a biomarker for chemo-immunotherapy response.","authors":"Thanpisit Lomphithak, Nattaya Duangthim, Sasiprapa Sonkaew, Siriporn Jitkaew","doi":"10.1186/s13062-025-00687-y","DOIUrl":"10.1186/s13062-025-00687-y","url":null,"abstract":"<p><strong>Background: </strong>Cholangiocarcinoma (CCA) is an aggressive malignancy with limited treatment options. Despite the approval of chemotherapy and immune checkpoint inhibitors (ICIs) in clinical practice, treatment outcomes remain poor, largely due to the poorly immunogenic tumor microenvironment associated with this type of carcinoma. Necroptosis, an inflammatory form of programmed cell death, has emerged as a promising therapeutic target for stimulating antitumor immunity. Our previous study linked necroptosis to increased CD8 + T cell infiltration and T cell-induced PD-L1 expression in CCA cells, suggesting its role in enhancing ICI efficacy. However, the underlying mechanisms by which necroptosis-activated T cells induce PD-L1 expression remain unclear. Here, we investigate how necroptosis in CCA cells influences T cell response, which subsequently promotes PD-L1 expression, thus providing insights for optimizing necroptosis-based therapies in combination with ICIs.</p><p><strong>Results: </strong>Conditioned medium from gemcitabine-induced necroptotic CCA cells triggers PBMC-derived T cell activation by upregulating the surface activation marker CD69 and promoting cytokine release, primarily IL-6 and IL-1β. This cytokine release subsequently induces PD-L1 expression in CCA cells via IL-6, as confirmed by IL-6 neutralizing antibodies. Furthermore, T cell killing assays demonstrated that pembrolizumab, an anti-PD-1 inhibitor, enhances T cell cytotoxicity against PD-L1-upregulated CCA cells. Additionally, bioinformatics analysis identified an IL-6 signaling-related gene signature associated with ICI responsiveness, suggesting potential biomarkers for personalized treatment strategies.</p><p><strong>Conclusion: </strong>This study highlights that necroptosis shapes the tumor immune microenvironment by promoting T cell activation and IL-6-mediated PD-L1 upregulation in CCA cells. These findings support the integration of necroptosis-based therapies with ICIs as a sequential chemo-immunotherapy strategy. Additionally, the identified IL-6 signaling-related gene signature may serve as a biomarker for patient stratification and personalized treatment in CCA.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"98"},"PeriodicalIF":4.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124259","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":"Single-cell transcriptome analysis suggests cells of the tumor microenvironment as a major discriminator between brain and extracranial melanoma metastases.","authors":"Konrad Grützmann, Michael Seifert","doi":"10.1186/s13062-025-00691-2","DOIUrl":"10.1186/s13062-025-00691-2","url":null,"abstract":"<p><strong>Background: </strong>Despite therapeutic advances, metastatic melanoma, and particularly brain metastasis (MBM), remains a lethal burden for patients. Existing single-cell studies offer a more detailed view of melanoma and its microenvironment, which is crucial to improve diagnosis and treatment.</p><p><strong>Results: </strong>We here present a computational reanalysis of single-nucleus data comparing 15 MBM and 10 extracranial melanoma metastases (ECM), considering recent best practice recommendations. We used cell type-specific pseudobulking and omit imputation during patient integration to gain complementary insights. Interestingly, our analysis revealed high homogeneity in tumor cell expression profiles within and between MBM and ECM. However, MBM displayed even higher homogeneity but a more flexible energy metabolism, suggesting a specific metastatic adaptation to the putatively more restricted brain microenvironment. While tumor cells were homogeneous, the metastasis microenvironment, especially lymphocytes and related immune-tumor interaction pathways, exhibited greater divergence between MBM and ECM. Overall, this suggests that major differences between MBM and ECM are potentially driven by variations in their microenvironment. Finally, a comparison of single-cell data to previous bulk studies, including their deconvoluted putative cell types, showed significant differences, potentially causing divergent conclusions.</p><p><strong>Conclusion: </strong>Our study contributed to refine the understanding of differences between MBM and ECM, suggesting these are potentially more influenced by their local microenvironments. Future research and therapies could possibly focus on the metabolic flexibility of melanoma brain metastases and patient-specific immune pathway alterations.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"97"},"PeriodicalIF":4.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069057","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":"Spleen granulopoiesis in psoriasis immune microenvironment aggravates psoriasis via IL-6/P-STAT3 signaling.","authors":"Feng Shi, Pixia Gong, Shan Huang, Weidong Zhu, Chenxi Shi, Chang Qi, Zhe Lei, Yayun Ding","doi":"10.1186/s13062-025-00675-2","DOIUrl":"10.1186/s13062-025-00675-2","url":null,"abstract":"<p><strong>Background: </strong>Psoriasis is an immune-mediated chronic inflammatory condition characterized by significant neutrophil infiltration in the skin. Given that the spleen is the largest peripheral immune organ in the body, it is important to investigate whether it has any impact on skin inflammation in psoriasis.</p><p><strong>Methods: </strong>To investigate this mechanism, a psoriatic mouse model was established by IMQ application. Flow cytometry and immunohistochemistry analyses were performed to determine the percentage of various immune cells in the spleen. The role of neutrophils was specifically assessed using the anti-Gr-1 antibody. Splenic granulopoiesis was evaluated using EdU labeling. To understand the spleen's role in skin inflammation, splenectomy was performed on the experimental mice. IL-6 levels were measured by ELISA, and P-STAT3 in neutrophils was detected via immunofluorescence. Further examination of IL-6's effects on neutrophil formation involved treating mice with IL-6 antibody. The severity of psoriasis was evaluated through histological staining and PASI scoring.</p><p><strong>Results: </strong>Our study revealed that the spleens of psoriatic mice were enlarged compared to those of vehicle mice. Among immune cell populations, neutrophils showed the most significant changes, with marked increases in both spleen and skin of psoriatic mice and patients, contributing to disease progression. Post-splenectomy, neutrophil infiltration in the skin was reduced by approximately 60% in psoriatic mice. This indicates that the neutrophils in the skin were primarily derived from the spleen. Additionally, the spleen showed a notable capacity for granulopoiesis with elevated neutrophils. Moreover, we found elevated IL-6 levels in the skin, blood, and spleen in the model, which was decreased after splenectomy. Treatment with an IL-6 antibody reduced neutrophil formation in both the spleen and skin, which alleviated skin inflammation in psoriatic mice. Additionally, P-STAT3 signaling was decreased following IL-6 antibody treatment. The neutrophil infiltration in spleen and skin was decreased after injection with the inhibitor of P-STAT3, which also alleviated the inflammation of psoriatic model. Thus, IL-6 served as the dominant regulator of spleen granulopoiesis, a process potentially mediated by P-STAT3 signaling.</p><p><strong>Conclusions: </strong>The spleen plays a crucial role in the immune microenvironment of psoriasis as a major site of granulopoiesis, influencing neutrophil infiltration in the skin of psoriatic mice. Additionally, IL-6 is a key regulator of neutrophil formation in the spleen of psoriatic mice, likely through P-STAT3-dependent mechanisms.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"96"},"PeriodicalIF":4.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943180","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":"Evolution of cell therapies derived from adipose tissue: historical perspectives, current development trends and future directions.","authors":"Silvia Gandolfi, Elise Lupon, Audrey Varin, Agnes Coste, Brigitte Sallerin, Carla Boyer, Yanis Berkane, Benoit Chaput","doi":"10.1186/s13062-025-00682-3","DOIUrl":"https://doi.org/10.1186/s13062-025-00682-3","url":null,"abstract":"<p><p>Over the last few decades, adipose tissue has attracted increasing attention in the field of regenerative medicine, thanks to discoveries related to its regenerative, anti-inflammatory, and pro-angiogenic properties. Over the years, with the advancement of sophisticated research around adipose tissue, there has been a shift from tissue transfer to cell transfer, and then to the application of cell-free derivatives and bioengineering. Understanding the evolution of this scientific revolution around adipose tissue not only helps clarify potential therapeutic products and indications but also allows us to discuss its limitations and future directions.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"95"},"PeriodicalIF":4.9,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943117","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":"Inhibition of PRC1 elicits immunogenic cell death by triggering ROS-dependent ER stress in colorectal cancer via the Wnt/β-catenin signaling pathway.","authors":"Wei Wang, Lijiang Zhou, Xinyu Zhang, Zheng Li","doi":"10.1186/s13062-025-00685-0","DOIUrl":"https://doi.org/10.1186/s13062-025-00685-0","url":null,"abstract":"<p><p>Due to the low response rate and severe side effects, the clinical efficacy of current immunotherapy for patients with colorectal cancer (CRC) remains unsatisfactory. Induction of immunogenic cell death (ICD) has been evidenced to be conducive to enhancing the survival benefit of immune checkpoint blockade (ICB) therapy. Protein regulator of cytokinesis 1 (PRC1) has been proven to be a tumor promoter in CRC and an immune marker. However, whether and how PRC1 is involved in the ICD regulation in CRC remains undiscovered. The current study identified the upregulation of PRC1 in CRC tissues and its prognostic value via bioinformatics analyses. Similarly, we determined the close correlation between PRC1 and ICD. In addition, knockdown of PRC1 induced ICD and downregulated PD-L1 expression in CRC cells, which was attenuated by ER stress inhibitor 4-PBA. PRC1 silencing elicited ER stress, but this effect was partially rescued by the ROS scavenger N-acetylcysteine. Mechanism investigation revealed that PRC1 could stimulate Wnt/β-catenin activation in CRC cells. According to results of rescue assays, activation of Wnt/β-catenin by BML-284 could partially reverse the effects of PRC1 knockdown on ER stress and ICD in CRC cells. Finally, the in vivo experiments demonstrated that silencing of PRC1 restrained tumor growth in CRC animal models. In conclusion, this study verified that inhibition of PRC1 expression could induce ICD in CRC by triggering ER stress via the Wnt/β-catenin signaling pathway. These findings highlight a novel molecular pathway whereby PRC1 exerts carcinogenic role in tumor immune microenvironment through ICD in CRC.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"94"},"PeriodicalIF":4.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12372356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943145","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":"Matrix stiffness induced gallbladder fibroblasts activation and paracrine SEMA7A promotes gallbladder cancer cell epithelial-mesenchymal transition and cancer stem cell-like properties by modulating AKT/p300 signalling.","authors":"Liankang Sun, Huanhuan Wang, Hanqi Li, Ruida Yang, Xuyuan Dong, Danfeng Dong, Yangwei Fan, Enxiao Li, Hao Wang, Yinying Wu, Yu Shi","doi":"10.1186/s13062-025-00683-2","DOIUrl":"10.1186/s13062-025-00683-2","url":null,"abstract":"<p><strong>Background & aims: </strong>Gallbladder cancer (GBC) is characterised by a desmoplastic microenvironment rich in collagen fibres and extracellular matrix, contributing to increased matrix stiffness. SEMAs are overexpressed in various cancers but their expression and role in the crosstalk between activated gallbladder fibroblasts (GFs) and GBC cells within a stiff microenvironment remain unclear. Herein, we aimed to elucidate the expression patterns and tumour-promoting effects of SEMAs in activated GFs under the matrix stiffness microenvironment.</p><p><strong>Methods: </strong>Masson staining assessed collagen deposition in GBC stroma. GFs were isolated from gallbladder tissues and cultured on silicon or polyacrylamide hydrogels. SEMA expression in GFs under different stiffness conditions was determined via RNA-seq and RT-qPCR. Transwell assays, tumorsphere-formation and Western blot assays were used to investigate the effects of GFs-derived SEMA7A on GBC epithelial-mesenchymal transition (EMT) and cancer stem-like traits. Subcutaneous tumour models were established by co-injecting GFs and GBC cells to assess SEMA7A's role in vivo. Co-immunoprecipitation, WB, Elisa and mutation assays were employed to elucidate the mechanism of SEMA7A involvement in GFs-GBC cell crosstalk.</p><p><strong>Results: </strong>This study revealed a high-stiffness microenvironment in GBC, inducing GFs activation and SEMA7A paracrine through YAP/TAZ signalling. GFs-secreted SEMA7A under matrix stiffness microenvironment promoted GBC EMT and cancer stem-like traits. Mechanistically, GFs-secreted SEMA7A bound to its receptor integrin β1 instead of plexinC1 on GBC cells to induce the phosphorylation of p300 at S1834 and maintain the malignant phenotypes of GBC cells. Moreover, the SEMA7A/integrin β1 axis-induced p300 phosphorylation at S1834 was mediated by Akt activation (p-Akt at S473) in GBC cells.</p><p><strong>Conclusions: </strong>Our findings demonstrate a complex stiffness/SEMA7A/integrin β1/AKT/p300 cascade mediating reciprocal interactions between GFs and GBC cells, offering a potential therapeutic target for patients with GBC.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"93"},"PeriodicalIF":4.9,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882179","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}