Cellular & Molecular Biology Letters最新文献

{"title":"α-tubulin N-acetyltransferase 1 regulates NCOA4-mediated ferritinophagy and protects cancer cells from ferroptosis.","authors":"Francesca Romana Pellegrini, Angela Iuzzolino, Cristina De Palma, Francesca Ambrosio, Giulia Fianco, Francesco Davide Naso, Alessio Paone, Serena Rinaldo, Francesca Cutruzzolà, Francesca Degrassi, Flavie Strappazzon, Venturina Stagni, Daniela Trisciuoglio","doi":"10.1186/s11658-026-00964-2","DOIUrl":"10.1186/s11658-026-00964-2","url":null,"abstract":"<p><strong>Background: </strong>Microtubules acetylation has emerged as a key regulator of cellular homeostasis, but its roles in autophagy remain understudied. Here, we identify α-tubulin acetyltransferase 1 (ATAT1), the enzyme responsible for α-tubulin K40 acetylation, as a critical regulator of NCOA4-mediated ferritinophagy and iron homeostasis in cancer cells.</p><p><strong>Methods: </strong>Human cancer cell lines were stably or transiently silenced for ATAT1 expression. Autophagy induction was evaluated by visualizing punctate structures and by analyzing changes in autophagic marker levels. Seahorse and flow cytometry experiments were conducted to study the impact of ATAT1 silencing on cell metabolism. Additionally, analysis of iron homeostasis genes, free iron pool, as well as colocalization of NCO4A and ferritin to autophagosome were analyzed to confirm activation of ferritinophagy. Finally, we treated cells with RSL3 (a ferroptosis inducer) and ferrostatin-1 or chloroquine to understand the connection between ATAT1, autophagy, and ferroptosis-induced cell death. Genetic approaches were used to study the role of NCO4A and K40 acetylation in these pathways.</p><p><strong>Results: </strong>We show that ATAT1 silencing induces an oxidative stress response accompanied by a functional autophagic flux. Notably, ATAT1-silenced cells exhibited reduced ATP production and oxygen consumption rate compared with control cells, as well as altered mitochondrial dynamics under both normal and stress conditions. Importantly, ATAT1 loss leads to intracellular iron overload by inducing NCOA4-mediated ferritinophagy, which targets the degradation of the iron storage protein ferritin, thus maintaining intracellular iron homeostasis. Activation of ferritinophagy, in turn, renders ATAT1-silenced lung cancer cells more susceptible to ferroptotic cell death. Notably, the key phenotypes observed in ATAT1-silenced cells are absent in cells with non-acetylatable α-tubulin, demonstrating a direct role for the loss of ATAT1 protein on the induction of a ferroptosis vulnerability phenotype.</p><p><strong>Conclusions: </strong>These findings challenge the traditional view of ATAT1 as a simple microtubule modifier and position this acetyltransferase as a central node in redox, metabolic, and autophagic regulation.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13520228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148239050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 role of ECM mechanics in cancer mechanotransduction through unraveling the molecular machinery of integrins, FAK, and YAP signaling.","authors":"Nourhan Hassan, Burkhard Greve, Martin Götte","doi":"10.1186/s11658-026-00905-z","DOIUrl":"10.1186/s11658-026-00905-z","url":null,"abstract":"<p><p>Mechanotransduction, the process by which cells convert mechanical stimuli into biochemical signals, is fundamental for maintaining tissue homeostasis and regulating physiological functions. The extracellular matrix (ECM) serves as a critical mediator of mechanotransduction, with its mechanical properties influencing cellular behaviour and function through complex molecular machinery. This comprehensive review examines the role of ECM mechanics in disease mechanotransduction, focusing on the molecular machinery of integrins, focal adhesion kinase (FAK) and YAP signaling pathways. We explore the structure and composition of the ECM, including detailed analysis of key components such as collagens, elastin, glycoproteins, proteoglycans, hyaluronic acid and matrix metalloproteinases. The review elucidates how integrins function as key mediators of mechanotransduction, the role of FAK in signal transduction, and the mechanosensitive functions of YAP/TAZ signaling. We examine the intricate crosstalk between these mechanotransduction pathways and their dysregulation in cancer. Finally, we discuss emerging therapeutic strategies targeting mechanotransduction pathways and the challenges and opportunities for translating mechanotransduction research into clinical interventions. Understanding these complex mechanotransduction networks is crucial for developing novel therapeutic approaches to treat diseases characterized by altered tissue mechanics and dysregulated cellular responses to mechanical cues.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13277065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148210301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chlorogenic acid mitigates calcium oxalate monohydrate crystal-induced epithelial-to-mesenchymal transition in renal epithelial cells via suppression of HSP60 expression and p38 signaling.","authors":"Paleerath Peerapen, Somsakul Phuangkham, Wanida Boonmark, Visith Thongboonkerd","doi":"10.1186/s11658-026-00975-z","DOIUrl":"10.1186/s11658-026-00975-z","url":null,"abstract":"<p><strong>Background: </strong>Epithelial-to-mesenchymal transition (EMT) is a prominent process involved in kidney fibrosis. Calcium oxalate monohydrate (COM), a crystalline composition predominantly found in renal stones, is one of the known stimuli that can trigger the EMT process. Chlorogenic acid (CGA), a phenolic hydroxycinnamate naturally found in several plants (especially coffee beans), has several health benefits, including antifibrotic properties. However, the mechanisms underlying its preventive effects against COM-induced EMT in renal epithelial cells remain unclear.</p><p><strong>Methods: </strong>Herein, Madin-Darby canine kidney (MDCK) renal epithelial cells were exposed to COM crystals without or with CGA pre-/cotreatment and were subjected to various assays, including morphological examination, measurement of cell spindle index, transepithelial resistance (TER) measurement, immunofluorescence staining of EMT markers, and western blotting of p38 signaling proteins. Additionally, label-free quantitative proteomics using nanoLC-ESI-LTQ-Orbitrap MS/MS and functional enrichment analyses were carried out, followed by functional validation of the essential role of heat shock protein 60 (HSP60) using a small interfering RNA (siRNA)-based knockdown method.</p><p><strong>Results: </strong>As expected, COM induced the EMT process as shown by increases in spindle index and mesenchymal marker (vimentin) but decreases in TER and epithelial marker (ZO-1). Mechanistically, these changes were accompanied with activation of p38 signaling. However, CGA pre-/cotreatment successfully prevented all these COM-induced changes. Label-free quantitative proteomics revealed significantly altered levels of 167 cellular proteins caused by COM. Among these, 55 proteins were completely preserved by CGA. Protein-protein interaction network illustrated HSP60 as a hub of these interacting proteins. While COM increased the HSP60 level, CGA successfully preserved this protein at its basal level. Moreover, knockdown of HSP60 expression by small interfering RNA could also prevent COM-induced EMT and p38 activation.</p><p><strong>Conclusions: </strong>These data indicate that CGA mitigates COM-induced EMT via suppression of HSP60 expression and p38 signaling activated by COM crystals.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148210331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPNMB-ECD drives acquired resistance to osimertinib in NSCLC via inducing tumor cell cytoskeletal reorganization.","authors":"Min Zhang, Jia-Qi Wang, Xiao Yang, Wen-Yi Liu, Yu-Tang Huang, Chun-Jie Wen, Dan Chen, Lan-Xiang Wu","doi":"10.1186/s11658-026-00965-1","DOIUrl":"10.1186/s11658-026-00965-1","url":null,"abstract":"<p><strong>Background: </strong>Acquired resistance constitutes a major obstacle to the efficacy of osimertinib therapy in nonsmall-cell lung cancer (NSCLC), yet its underlying mechanisms remain incompletely understood. While the soluble extracellular domain of GPNMB (GPNMB-ECD) is recognized as a driver of tumor progression, its involvement in acquired resistance to osimertinib remains unknown.</p><p><strong>Purpose: </strong>This study aimed to investigate the role of GPNMB-ECD in acquired osimertinib resistance in NSCLC.</p><p><strong>Methods: </strong>The expression dynamics of GPNMB in osimertinib-sensitive (OS) and osimertinib-resistant (OR) NSCLC tissues and cell lines were profiled using single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq, respectively. Full-length GPNMB and GPNMB-ECD levels in tumor tissues and patient plasma were assessed by immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). In vitro, the impact of GPNMB-ECD on osimertinib sensitivity was evaluated using CCK-8, colony formation, flow cytometry, and transwell assays. Correspondingly, in vivo effects were investigated in nude mouse models of subcutaneous and pulmonary metastasis. The underlying mechanisms were explored through co-immunoprecipitation (Co-IP), immunofluorescence, and transmission electron microscopy (TEM). Finally, the therapeutic efficacy of the anti-GPNMB-ECD antibody was evaluated in humanized patient-derived xenograft (huPDX) models.</p><p><strong>Results: </strong>Tumor cells exhibited elevated GPNMB expression in OR tissues compared with OS controls and emerged as the primary source of GPNMB-ECD within the OR TME. Plasma levels of GPNMB-ECD were substantially higher in patients with OR NSCLC compared with patients with OS NSCLC, suggesting this marker as a potential indicator of acquired resistance and poor prognosis. Functional studies confirmed that GPNMB-ECD promotes osimertinib resistance both in vitro and in vivo. Mechanistically, GPNMB-ECD engages syndecan-4 (SDC4) on tumor cells, triggering SDC4 phosphorylation, F-actin reorganization, and Yes-associated protein (YAP) nuclear translocation, thereby upregulating pro-tumorigenic genes and reducing osimertinib sensitivity. Crucially, anti-GPNMB-ECD antibodies restored osimertinib sensitivity in huPDX models established from human NSCLC tumors.</p><p><strong>Conclusions: </strong>Our findings define GPNMB-ECD-driven resistance as a novel paradigm in NSCLC and identify a viable precision therapeutic strategy to overcome it.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13520340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneity of macrophages in PD-1/PD-L1 inhibitor therapy: a single-cell perspective.","authors":"Jinjing Wu, Dan Zhou, Kunpeng Jiang, Zhenkui Li, Yudi Yao, Shaqi Rao, Xiaohong Yang, Daya Luo","doi":"10.1186/s11658-026-00956-2","DOIUrl":"10.1186/s11658-026-00956-2","url":null,"abstract":"<p><p>Therapeutic blockade of the PD-1/PD-L1 signaling pathway is the focus of tumor immunotherapy. However, drug resistance and irAEs induced by PD-1/PD-L1 inhibitors have emerged as major limitations affecting survival outcomes in patients with cancer. Macrophages are not only the core immune cells that regulate tumor progression and metastasis, but also the key factors that affect the therapeutic effect of PD-1/PD-L1 inhibitors, thus showing significant clinical value in optimizing immunotherapy strategies. scRNA-seq technology has provided powerful analytical tools and precise biological insights to decipher macrophage heterogeneity, further elucidating disease-specific macrophage subpopulations with distinct gene signatures and functional plasticity during PD-1/PD-L1 blockade therapy. These advances have paved the way for better understanding the mechanisms underlying immunotherapy-induced toxicities and identifying novel predictive biomarkers. Herein, we comprehensively summarize the multifaceted functional roles of macrophages in PD-1/PD-L1 inhibitor-mediated antitumor efficacy, drug resistance and irAEs from a single-cell perspective, and the potential value of targeting macrophages to improve the accuracy of immunotherapy.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13274014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZNF662 inhibits oncogenesis through NUPR1/p53 signaling pathway in epithelial ovarian cancer and is regulated by hsa-miR-429.","authors":"Zhen Huang, Hongxue Fu, Ling Li, Wenjing Liao, Jing Zhang, Qin Tang, Mao Huang, Tingxiu Xiang, Liangdan Tang","doi":"10.1186/s11658-026-00958-0","DOIUrl":"10.1186/s11658-026-00958-0","url":null,"abstract":"<p><strong>Background: </strong>Epithelial ovarian cancer (EOC) represents the most lethal malignancy of the female reproductive system, though its etiology and pathogenesis remain incompletely characterized. The Krüppel-associated box domain zinc finger protein (KRAB-ZNF) family, the largest transcription factor family in mammals, plays critical roles in malignant tumor development and progression. This study aimed to investigate the clinical significance and molecular mechanisms of ZNF662 in EOC pathogenesis.</p><p><strong>Methods: </strong>ZNF662 expression patterns and their association with clinicopathological features and prognosis were analyzed using integrated bioinformatics (The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), CSIOVDB, Kaplan-Meier Plotter) and clinical tissue specimens. Functional impacts on proliferation, migration, invasion, apoptosis, and cell cycle progression were assessed then. Mechanistic studies delineating upstream regulators and downstream effectors employed transcriptome sequencing, dual-luciferase reporter assays, chromatin immunoprecipitation (ChIP), and functional validation experiments.</p><p><strong>Results: </strong>ZNF662 expression was downregulated in ovarian cancer tissues, correlating with advanced tumor stage, ascites presence, and poor overall survival. Functional assays demonstrated that ZNF662 suppressed proliferation, migration, and invasion of ovarian cancer cells while promoting apoptosis and inducing G0/G1 cell cycle arrest. Bioinformatics analysis and dual-luciferase reporter assays confirmed that hsa-miR-429 directly binds to the 3'-untranslated region (UTR) of ZNF662, downregulating its expression and promoting malignant behaviors. Transcriptomic and mechanistic validation revealed that ZNF662 transcriptionally represses NUPR1 and activates the p53 signaling pathway, thereby inhibiting the malignant phenotype of EOC.</p><p><strong>Conclusions: </strong>The hsa-miR-429/ZNF662/NUPR1/p53 pathway axis critically regulates EOC pathogenesis. ZNF662 represents a promising diagnostic biomarker and therapeutic target for EOC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphoproteomic profiling reveals post-translational dysregulation in Huntington's disease patient-derived neurons.","authors":"Lea Danics, Chandramouli Muralidharan, Ágnes Varga, Melinda Rezeli, Jeovanis Gil, Anna A Abbas, Ádám Pap, Andrew S Park, Marcell Cserhalmi, Emilie M Legault, Ármin Sőth, Dorina Jamniczky, Roland Zsoldos, Roger A Barker, Gergely Róna, Janelle Drouin-Ouellet, György Markó-Varga, Zsuzsanna Darula, Karolina Pircs","doi":"10.1186/s11658-026-00948-2","DOIUrl":"10.1186/s11658-026-00948-2","url":null,"abstract":"<p><p>Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin gene. Although transcriptomic and proteomic changes have been characterized in patient-derived neurons, the contribution of post-translational modifications, such as phosphorylation, remains poorly understood. Here, we present the first phosphoproteomic analysis by mass spectrometry (P-MS) of human induced neurons (iNs) directly reprogrammed from HD patient fibroblasts. We identified 177 phosphopeptides with significantly altered abundance in HD-iNs, mapping to phosphoproteins associated with key signaling pathways known to be affected in HD, such as splicing and autophagy. By integrating P-MS data with previously published proteomic and transcriptomic data from the same donors, we identified distinct subsets of ON-OFF phosphopeptides that exhibited a complete loss of phosphorylation in either HD- or control-iNs, without corresponding changes at the RNA or protein level. An exception was MXRA8, previously described in glial cells as a mediator of blood-brain barrier integrity and astrocyte-mediated neuroinflammation. This protein showed increased protein abundance despite the absence of phosphorylation in HD-iNs, suggesting a compensatory mechanism. In addition, MXRA8 showed altered protein-protein interactions with lysosomal and metabolic regulators in HD-iNs, highlighting its potential role in autophagy impairment as well as in neurovascular dysfunction. These findings uncover a distinct layer of post-translational dysregulation in HD, suggesting that phospho-switch proteins such as MXRA8 may be candidate effectors of pathology, and thus, site-specific phosphorylation loss may contribute to impaired signaling and proteostasis in human HD neurons.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13445741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deorphanisation and functional characterisation of OATP5A1 as transport protein for amino acids and vitamins.","authors":"Elena Kohlmann, Nikola K Schmid, Arne Gessner, Martin F Fromm, Jörg König","doi":"10.1186/s11658-026-00943-7","DOIUrl":"10.1186/s11658-026-00943-7","url":null,"abstract":"<p><strong>Background: </strong>Transport proteins are important for the uptake, distribution and elimination of endogenous substances and drugs, and therefore essential for, e.g., cellular metabolism or drug effects. While the export of substrates out of cells is mediated by ATP-binding cassette (ABC) transporters, SLC (solute carrier) transporters are mainly responsible for the uptake into cells. In contrast to most well-characterised ABC transporters, many SLC transporters have been studied insufficiently. Such transporters are called orphan transporters. Despite the fact that the SLC21/SLCO family contains several important transporters for widely prescribed drugs, one of its family members, OATP5A1 (SLCO5A1), is such an orphan transporter. OATP5A1 is ubiquitously expressed throughout the body, including expression in the brain, heart, intestine and various cancerous tissues. However, no substrates have been characterised for this transporter to date.</p><p><strong>Methods: </strong>Using stably-transfected HEK293 cells overexpressing human OATP5A1 (HEK-OATP5A1) and the respective control cells (HEK-VC), we investigated known substrates of other OATP family members as potential OATP5A1 substrates. Furthermore, an untargeted metabolomics analysis of both cell lines was performed after incubation with human plasma. Candidate substances were further characterised as substrates of OATP5A1.</p><p><strong>Results: </strong>After characterisation of the stably-transfected HEK-OATP5A1 cells, uptake assays and untargeted metabolomics analysis identified the hormone conjugate estrone-3-sulfate, the amino acids glutamine, glycine and tyrosine, the vitamins pantothenic acid (vitamin B₅) and thiamine (vitamin B₁) and the nucleotide thymine as potential OATP5A1 substrates. While estrone-3-sulfate, tyrosine and thiamine were further characterised as uptake substrates, glutamine and glycine were exported by OATP5A1. Moreover, pantothenic acid and thymine inhibited OATP5A1-mediated tyrosine uptake. For estrone-3-sulfate, tyrosine and thiamine, kinetic transport parameters (K_m values) of 102.2 µM, 169.9 µM and 15.6 µM were calculated, respectively.</p><p><strong>Conclusions: </strong>In the present study, OATP5A1 was deorphanised by characterising amino acids and vitamins as substrates of this transport protein. Estrone-3-sulfate, tyrosine and thiamine were taken up by OATP5A1. Moreover, OATP5A1 mediated the efflux of the amino acids glutamine and glycine, which play essential roles in brain function.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"31 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13231527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate-activated astrocytes promote NSCLC brain metastasis through extracellular vesicle-mediated miR-8085/TRIM67/ELK1 signaling axis.","authors":"Haiqin Peng, Guilong Tanzhu, Wen Shi, Gang Xiao, Qian Zeng, Liu Chen, Xin Wan, Di Jing, Haibin Deng, Thomas Michael Marti, Jun Fu, Rongrong Zhou","doi":"10.1186/s11658-026-00957-1","DOIUrl":"10.1186/s11658-026-00957-1","url":null,"abstract":"<p><p>Brain metastasis represents an advanced complication in non-small cell lung cancer (NSCLC), characterized by therapeutic resistance and dismal survival outcomes. Although astrocytes are known to influence tumor progression within the brain microenvironment, their prognostic significance and mechanistic contributions to NSCLC brain metastasis (NSCLC-BM) remain largely unresolved. In this study, we analyze brain metastatic tumors from 66 patients with NSCLC and demonstrate that high infiltration of astrocytes is significantly associated with reduced overall survival. Functional assays reveal that astrocytes enhance the stemness of metastatic tumor cells, a phenotype that is significantly attenuated by silencing astrocytic monocarboxylate transporter 1 (MCT1), thereby blocking lactate uptake. Mechanistically, lactate reprograms astrocytes to release extracellular vesicles enriched in miR-8085, which downregulates the E3 ubiquitin ligase TRIM67 in tumor cells. This suppression stabilizes the transcription factor ELK1 through inhibition of ubiquitin-mediated degradation, promoting stemness maintenance and tumorigenic capacity. Clinically, low TRIM67 and high ELK1 expression correlate with poorer survival in patients with NSCLC-BM. Together, our findings uncover a novel lactate-induced miR-8085/TRIM67/ELK1 signaling cascade that drives brain metastasis progression and highlight potential prognostic biomarkers and therapeutic targets for patients with NSCLC involving the brain.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KAP1 SUMOylates and stabilizes SR-A to facilitate glycated LDL transcytosis and accelerate atherosclerosis.","authors":"Meng Shu, Wenzhuo Cheng, Fangyang Yu, Liyin Zhang, Li Wang, Yan Shu, Ruonan Wang, Baorui Xue, Si Jin","doi":"10.1186/s11658-026-00954-4","DOIUrl":"10.1186/s11658-026-00954-4","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis (AS)-associated cardiovascular disease is the main cause of global mortality. The excessive retention of glycated low-density lipoprotein (G-LDL) under the vascular endothelium promotes AS. In addition, G-LDL supports a role in promoting the expression of scavenger receptor A (SR-A), increasing SR-A-mediated transcytosis of G-LDL in endothelial cells (ECs), consequently accelerating the progression of atherosclerosis. However, the underlying mechanism used by G-LDL to promote SR-A expression has not been elucidated, thus representing the aim of this work.</p><p><strong>Methods: </strong>The protein-protein interaction of the E3 SUMO ligase KRAB structural domain-associated protein 1 (KAP1) and SR-A were confirmed by co-immunoprecipitation (co-IP)-based immunoblotting and immunofluorescence in human umbilical vein endothelial cells (HUVECs). G-LDL uptake and transcytosis in KAP1-silencing or overexpressing HUVECs were assessed. The effect of KAP1 on de-ubiquitination and SUMOylation of SR-A was determined by co-IP-based immunoblotting. The role of KAP1 on G-LDL-induced atherosclerosis was tested by adenovirus-mediated knockdown in ApoE^-/- mice.</p><p><strong>Results: </strong>KAP1 was identified as an enhancer of SR-A, promoting its expression. KAP1 bound to SR-A and promoted SUMO1 modification of the SR-A lysine (K)22, which hampers K48-linked ubiquitination and proteasomal degradation of SR-A. KAP1 deficiency attenuated G-LDL-induced SR-A activation both in vitro and in vivo, reduced aortic G-LDL retention, and consequently, atherosclerotic vulnerable plaque formation in murine models.</p><p><strong>Conclusions: </strong>This study identifies a SUMOylation-ubiquitination crosstalk that governs SR-A stability, revealing KAP1 as a key molecular switch controlling SR-A turnover in endothelial cells. These findings provide a mechanistic basis for how G-LDL accelerates atherosclerosis.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148101185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}