Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"Oncogenic HNF4α inhibits ferroptotic cell death through activating SLC7A11 by recruiting p300/CBP in breast cancer","authors":"Zhuang Wang ,&nbsp;Sen Xu ,&nbsp;Jinxia Hu ,&nbsp;Hongfang Sun ,&nbsp;Yuan Yu ,&nbsp;Shuling Song ,&nbsp;Shuyang Xie ,&nbsp;Guangbin Sun","doi":"10.1016/j.bbadis.2025.167884","DOIUrl":"10.1016/j.bbadis.2025.167884","url":null,"abstract":"<div><div>As an iron-dependent novel form of cell death caused by the accumulation of lipid peroxides, ferroptosis has been gradually recognized as a new cancer therapeutic target in recent years. Although the precise mechanisms underlying iron-induced cell death remain incompletely elucidated, this study identifies its distinctive role. A decrease in hepatocyte nuclear factor 4-alpha (HNF4α) activity could increase ferroptosis in breast cancer (BC) cells both in vitro and in vivo. Mechanistically, it was found that HNF4α binds directly to the promoter of SLC7A11, where it recruits the histone acetyltransferase p300/CBP to promote transcription of SLC7A11. Our study shows that HNF4α is crucial for ferroptosis in breast cancer, which may open up the possibility of developing a new therapeutic approach for advanced cancers resistant to chemotherapy.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167884"},"PeriodicalIF":4.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901989","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":"Integrated transcriptomics profile reveals the role of Gal-1 and miR-21 in intrahepatic cholangiocarcinoma progression","authors":"Huasong Yu ,&nbsp;Huahong Duan ,&nbsp;Ruiqi He ,&nbsp;Yu Tian ,&nbsp;Jiayang Jiang ,&nbsp;Fen Xiao ,&nbsp;Qiao Liu ,&nbsp;Jie Liu ,&nbsp;Hao Li ,&nbsp;Xing Yu","doi":"10.1016/j.bbadis.2025.167882","DOIUrl":"10.1016/j.bbadis.2025.167882","url":null,"abstract":"<div><div>Intrahepatic cholangiocarcinoma (ICC) is a highly invasive liver tumor with a poor prognosis, arises from the intrahepatic bile ducts. It is the second most common type of liver cancer. Understanding the mechanisms driving ICC progression is crucial for identification of biomarkers and therapeutic targets. Galectin-1 (Gal-1), encoded by the LGALS1 gene, is known to be upregulated in various malignancies and plays a significant role in cancer progression. However, its underlying mechanisms in ICC have yet to be fully elucidated. The study employed RNA-seq analysis, western blot, cell migration, colony forming, EdU assay, qRT-PCR, luciferase assay and mIHC to investigate the expression pattern of Gal-1 in ICC and its role in the progression of the disease. Our findings revealed a significant upregulation of Gal-1 in ICC tissues. Notably, downregulation of Gal-1inhibited ICC cell proliferation and migration. Further, Gal-1 appears to promote ICC progression through miR-21/STAT3-related pathways, playing a critical role to the tumor microenvironment. These results suggest that Gal-1 may serve as a promising molecular diagnostic marker and therapeutic target for ICC.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167882"},"PeriodicalIF":4.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899155","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":"Endosialin-directed CAR-T cell therapy: A promising approach for targeting triple-negative breast cancer","authors":"Adil Farooq Wali ,&nbsp;Sirajunisa Talath ,&nbsp;Sathvik B. Sridhar ,&nbsp;Mohamed El-Tanani ,&nbsp;Imran Rashid Rangraze","doi":"10.1016/j.bbadis.2025.167852","DOIUrl":"10.1016/j.bbadis.2025.167852","url":null,"abstract":"<div><div>In triple-negative breast cancer, this review article explores into the utilization of Chimeric antigen receptor T-cell (CAR-T) cell therapy to target cells expressing endosialin. Even with all the new treatments available, breast cancer still kills more women than any other disease. Drug resistance and ineffective cancer cell targeting are two major problems with targeted medications, chemotherapy, and surgery. Among cancer treatments, CAR-T cell therapy stands out. To identify endosialin as a therapeutic target, it is essential to understand its molecular structure and its involvement in tumor angiogenesis and progression. An effective target for CAR-T cells is breast cancer, which overexpresses endosialin. The development of CARs that are specific to endosialin and the results of early trials are covered in relation to CAR-T cell therapy that targets endosialin. Perhaps the most effective cancer treatment is endosialin targeting, since it is expressed only in tumors and plays a crucial role in the course of cancer. This article reviews endosialin-directed CAR-T cell breast cancer treatments' safety and efficacy from current and completed clinical trials. Despite promising results, these trials reveal that clinical translation must overcome significant challenges. The report suggests further research and combination tactics to improve endosialin-targeted CAR-T cell treatment.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167852"},"PeriodicalIF":4.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929491","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":"Quercetin induces keratinocytes apoptosis via triple inhibition of Notch, PI3K/AKT signaling and Glut1 in the treatment of psoriasis","authors":"Bai-lin Chen ,&nbsp;Wei-ming Zhang ,&nbsp;Xiao-wan Dong ,&nbsp;Jia-yi Liu ,&nbsp;Yan-ping Bai","doi":"10.1016/j.bbadis.2025.167879","DOIUrl":"10.1016/j.bbadis.2025.167879","url":null,"abstract":"<div><h3>Background</h3><div>Psoriasis is an immune-mediated inflammatory skin disorder marked by excessive keratinocyte proliferation and inflammatory cell infiltration. Quercetin has shown a range of biological activities, highlighting its potential as a therapeutic agent for psoriasis.</div></div><div><h3>Purpose</h3><div>This study aims to explore the mechanisms by which quercetin treats psoriasis.</div></div><div><h3>Methods</h3><div>An Imiquimod-induced psoriasis mouse model and a TNF-α-induced keratinocyte proliferation model were utilized, supplemented with quercetin and DAPT. The expression of K10, K14, Notch1, NICD, AKT and Glut1 in psoriatic lesions and normal skin was assessed. Techniques employed included hematoxylin-eosin staining, immunohistochemical staining, western blotting, quantitative polymerase chain reaction, cell counting kit-8 assay, flow cytometry, and enzyme-linked immunosorbent assay.</div></div><div><h3>Results</h3><div>Notch1, AKT, and Glut1 were highly expressed in psoriasis. Quercetin induced keratinocyte apoptosis and inhibited the Notch signaling pathway, as well as the expression of AKT and Glut1. Inhibition of Notch signaling led to keratinocyte apoptosis and downregulation of the AKT and Glut1 expression. The results of network pharmacology and molecular docking are consistent with this.</div></div><div><h3>Conclusion</h3><div>This study provides the first evidence that quercetin induces keratinocyte apoptosis and promotes keratinocyte differentiation to treat psoriasis through the triple inhibition of the Notch and PI3K/AKT signaling pathways, as well as Glut1. The downregulation of the PI3K/AKT pathway and Glut1 is achieved partially via Notch inhibition. These findings suggest that quercetin could be a novel agent for improving psoriasis treatment, especially in patients exhibiting high expression of Notch1, AKT, and Glut1 in their skin lesions.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167879"},"PeriodicalIF":4.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912162","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":"Angiogenesis and immune microenvironment in triple-negative breast cancer: Targeted therapy","authors":"Ying Zhang,&nbsp;Hao Yang,&nbsp;Yanhong Jiang,&nbsp;Yijing Jiang,&nbsp;Renfang Mao","doi":"10.1016/j.bbadis.2025.167880","DOIUrl":"10.1016/j.bbadis.2025.167880","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that typically lacks effective targeted therapies, leading to limited treatment options. Chemotherapy remains the primary treatment modality; however, in recent years, new immunotherapy approaches, such as immune checkpoint inhibitors, have shown positive results in some patients. Although the development of TNBC is closely associated with BRCA gene mutations, the tumor immune microenvironment (TIME) plays a crucial role in tumor progression and immune escape. Tumor angiogenesis, the accumulation of immunosuppressive cells, and alterations in immune molecules collectively shape an environment unfavorable for anti-tumor immune responses. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) promote immune escape by secreting immunosuppressive factors. Therefore, combination strategies of anti-angiogenic and immune checkpoint inhibitory therapies have shown synergistic effects in clinical trials, while new targeted therapies such as TGF-β inhibitors and IL-1β inhibitors offer new options for TNBC treatment. With the development of personalized medicine, combining immunotherapy and targeted therapies brings new hope for TNBC patients.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167880"},"PeriodicalIF":4.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906269","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":"DSG2 attenuates gemcitabine efficacy through PTX3 in lung adenocarcinoma","authors":"Chin-Chou Wang ,&nbsp;Jo-Ying Lin ,&nbsp;Chih-Yang Wang ,&nbsp;Wan-Jou Shen ,&nbsp;Pin-Chen Liao ,&nbsp;Yu-Fang Ho ,&nbsp;Che-Wei Lin ,&nbsp;Shao-An Wang ,&nbsp;Ching-Chung Ko ,&nbsp;Sanskriti Dey ,&nbsp;Hoang Dang Khoa Ta ,&nbsp;Do Thi Minh Xuan ,&nbsp;Sachin Kumar ,&nbsp;Bianca Tobias William ,&nbsp;Ju-Ming Wang ,&nbsp;Wei-Jan Wang","doi":"10.1016/j.bbadis.2025.167881","DOIUrl":"10.1016/j.bbadis.2025.167881","url":null,"abstract":"<div><div>Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer, often diagnosed at an advanced stage with poor prognosis and limited treatment options. The Desmoglein (DSG) family plays a crucial role in maintaining cell adhesion and tissue integrity. Upregulation of DSG proteins has been implicated in tumorigenesis, invasion, and metastasis across various cancers. However, the role of DSG in lung cancer, particularly as a biomarker influencing the efficacy of anti-cancer drugs, remains unclear. In this study, DSG2 was significantly overexpressed in LUAD tumor tissues and correlated with poor prognosis, as revealed by TCGA database analysis. Additionally, analyses of single-cell sequencing, KEGG, and GSEA multi-omics databases demonstrated that DSG2 modulates multiple oncogenic pathways, particularly the apoptosis pathway, with a strong positive correlation between DSG2 and PTX3 expression. In vitro experiments showed that DSG2 knockdown enhanced gemcitabine-induced apoptosis by downregulating the NFκB/STAT3/PTX3 signaling axis. Furthermore, adding recombinant PTX3 protein in DSG2 knockdown cells restored STAT3 activation, reducing gemcitabine efficacy, indicating that DSG2 contributes to gemcitabine resistance through PTX3-mediated mechanisms. This study identifies DSG2 as a critical mediator of gemcitabine resistance in LUAD through its regulation of the PTX3/NFκB/STAT3 pathway. The findings suggest that targeting DSG2 could enhance the therapeutic efficacy of gemcitabine in LUAD patients, offering a novel therapeutic strategy and biomarker for overcoming chemoresistance in this aggressive cancer subtype.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167881"},"PeriodicalIF":4.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143922852","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":"Exploring the role of the CD74+ cardiac macrophage subset in trastuzumab cardiotoxicity and its mechanisms","authors":"Minyan Zhu ,&nbsp;Yaping Yang ,&nbsp;Xinchen Tang ,&nbsp;Huan Hou ,&nbsp;Yan Zhang ,&nbsp;Rong Chen","doi":"10.1016/j.bbadis.2025.167875","DOIUrl":"10.1016/j.bbadis.2025.167875","url":null,"abstract":"<div><div>Trastuzumab (TRZ) is the standard treatment for human epidermal growth factor receptor 2 (HER-2) positive breast cancer, but its cardiotoxicity significantly impacts the prognosis and quality of survival of patients, and the underlying mechanism of TRZ-related cardiotoxicity remains incompletely understood. Macrophage subsets better reflect macrophage heterogeneity than the traditional macrophage M1/M2 type polarization classification. CD74, a receptor with strong binding affinity for macrophage migration inhibitory factor, plays an important role in macrophage activation. After successfully constructing a mouse TRZ cardiotoxicity model, flow cytometry indicated that CD74⁺ cardiac macrophages (CMφs) were significantly elevated in the TRZ group. Single-cell data were utilized to identify CD74⁺ CMφs, GO and KEGG analyses of the DEGs were conducted to further validate the CD74/STAT1 signaling pathway. Analyses using RT-PCR, immunofluorescence, and western blot revealed a marked increase in the expression of genes and proteins linked to this pathway in TRZ-treated group. Additionally, levels of inflammation-related factors and the expression of apoptotic proteins was elevated following TRZ treatment. CD74-knockdown RAW 264.7 macrophages cell line were constructed via Lentiviruses carrying CD74 (hU6-MCS-CBh-gcGFP-IRES-puromycin) transfection and co-cultured with HL-1 cardiomyocytes to establish an in vitro TRZ cardiotoxicity model. Western blot analysis of CD74/STAT1 signaling pathway protein levels demonstrated that CD74 knockdown rescued TRZ-induced cellular damage. These findings suggest that TRZ may promote inflammation and apoptosis in cardiomyocytes, leading to cardiotoxicity through the CD74⁺ CMφ subset, which regulates the CD74/STAT1 signaling pathway. CD74⁺ CMφs are anticipated to be a novel intervention target and therapeutic strategy for addressing TRZ-induced cardiotoxicity.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167875"},"PeriodicalIF":4.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899156","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":"Scientometric analysis of evolution in sex-specific MSC therapy for cardiovascular diseases","authors":"Elika Verma,&nbsp;Mehak Gupta,&nbsp;Riley Sierhuis,&nbsp;Sanjiv Dhingra","doi":"10.1016/j.bbadis.2025.167878","DOIUrl":"10.1016/j.bbadis.2025.167878","url":null,"abstract":"<div><h3>Background</h3><div>Mesenchymal stem cell (MSC) therapy for cardiovascular diseases has shown promise; however, sex-specific differences remain understudied. This scientometric analysis provides the first comprehensive overview of sex-specific differences in mesenchymal stem cell (MSC) therapy for cardiovascular diseases, spanning from 1947 to 2024.</div></div><div><h3>Methods</h3><div>We analyzed 61,029 publications using advanced bibliometric tools to identify research hotspots, publication trends, and collaborative networks.</div></div><div><h3>Results</h3><div>A significant shift in research focus has been observed in the field of mesenchymal stem cell (MSC) therapy for cardiovascular diseases, transitioning from broad cardiovascular concepts in the 20th century to specialized sex-specific considerations in the 21st century. Furthermore, in the 21st-century research landscape, the formation of two distinct clusters for “male” and “female” in VOSviewer-generated network visualizations is highly important, emphasizing the growing recognition of sex-specific differences in MSC therapy responses and outcomes. This shift was accompanied by a marked increase in terminology related to sex-specific differences, with keywords like “genetic association” and “body mass index” forming distinct clusters in recent years.</div></div><div><h3>Conclusions</h3><div>This analysis underscores the critical need for sex-specific considerations in MSC therapy for cardiovascular disease. The emergence of distinct male and female clusters in research networks emphasizes the importance of tailoring approaches based on sex differences. Key areas identified for future investigation include the role of epigenetics in mediating sex-specific effects and the potential of sex-matched MSC-derived exosomes. These findings pave the way for more effective and personalized approaches in cardiovascular regenerative medicine, potentially leading to improved outcomes through sex-specific therapeutic strategies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167878"},"PeriodicalIF":4.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143895760","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":"Docosahexaenoic acid prevents peroxisomal and mitochondrial protein loss in a murine hepatic organoid model of severe malnutrition","authors":"José M. Horcas-Nieto ,&nbsp;W. Alfredo Rios-Ocampo ,&nbsp;Miriam Langelaar-Makkinje ,&nbsp;Rinse de Boer ,&nbsp;Albert Gerding ,&nbsp;Serhii Chornyi ,&nbsp;Ingrid A. Martini ,&nbsp;Justina C. Wolters ,&nbsp;Ronald J.A. Wanders ,&nbsp;Hans R. Waterham ,&nbsp;Ida J. Van der Klei ,&nbsp;Robert H.J. Bandsma ,&nbsp;Johan W. Jonker ,&nbsp;Barbara M. Bakker","doi":"10.1016/j.bbadis.2025.167849","DOIUrl":"10.1016/j.bbadis.2025.167849","url":null,"abstract":"<div><h3>Introduction</h3><div>Acute and chronic exposure of cells to low amino acid conditions have been shown to lead to a reduction in hepatic peroxisomal and mitochondrial content. There is limited understanding of the underlying mechanisms behind this loss, but data suggests degradation through autophagy. Both organelles play a key role in fatty acid metabolism, which may explain why dysfunction in either one of them might lead to hepatic steatosis.</div></div><div><h3>Methods</h3><div>Using a previously established murine hepatic organoid model of severe malnutrition, we characterized the effects of prolonged amino-acid restriction on peroxisomal and mitochondrial protein levels and on autophagic flux. To do so, we developed concatemers of ¹³C-labelled peptide standards for quantification of over 50 different peroxisomal proteins. To assess the autophagic flux, we transduced hepatic organoids with a GFP-LC3-RFP-LC3ΔG probe. Finally, the effect of PPAR-α activation on peroxisomal loss was determined with various agonists.</div></div><div><h3>Results</h3><div>Prolonged (96 h) amino-acid restriction led to a more severe loss of peroxisomes than a 48 h restriction, and with a substantial induction of autophagic flux. This was accompanied by accumulation of intracellular triglycerides, loss of mitochondrial and peroxisomal proteins, and loss of peroxisomal functionality. While PPAR-α agonists WY-14643 and linoleic acid (LA) had no effect, docosahexaenoic acid (DHA) supplementation partly prevented peroxisomal and mitochondrial loss under amino-acid restricted conditions and partly inhibited autophagy.</div></div><div><h3>Discussion</h3><div>The potential of DHA to prevent loss of peroxisomes and mitochondrial functions in low protein diets and severe malnutrition warrants further causal and translational testing in preclinical models and clinical trials, including its use as nutritional supplement.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167849"},"PeriodicalIF":4.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143881305","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":"Cisplatin reduces immunosuppression caused by tumor-associated macrophages through downregulating CD47-SIRPα signaling in glioblastoma","authors":"Yanyan Li ,&nbsp;Yufei Cao ,&nbsp;Linyan He ,&nbsp;Jie Wu ,&nbsp;Lize Cai ,&nbsp;Youxin Zhou ,&nbsp;Haiying Li ,&nbsp;Wei Yang ,&nbsp;Ting Sun","doi":"10.1016/j.bbadis.2025.167876","DOIUrl":"10.1016/j.bbadis.2025.167876","url":null,"abstract":"<div><div>The poor prognosis of glioblastoma (GBM) is partly attributed to the immunosuppressive microenvironment. The combination of standard temozolomide and other chemotherapy drugs can significantly enhance the therapeutic effect by reshaping the immune microenvironment. Cisplatin treatment induces immunogenic cell death in tumor cells, stimulating an immune response. Here, we investigated the immune-activating effect of cisplatin on tumor-associated macrophages (TAMs). The therapeutic benefit of temozolomide plus cisplatin was showed in a murine model of GBM, accompanied by the inhibition of tumor growth and enhancement of pro-inflammatory activation of TAMs. Furthermore, cisplatin treatment downregulated the expression of CD47 in glioma stem cells, SIRPα, and IL-6 in TAMs, thus promoting M1-like polarization of TAMs to enhance an immune-activating tumor microenvironment. Mechanically, cisplatin decreases the production of lactic acid by downregulating LDHA expression. A low level of lactate reduces histone H3K18 lactylation on the CD47 and IL-6 promoters, thereby suppressing gene transcription. Our study reveals a new mechanism by which cisplatin remodels the immune tumor microenvironment, suggesting that combining temozolomide with cisplatin chemotherapy may be a new treatment option for GBM.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167876"},"PeriodicalIF":4.2,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912163","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}