Molecular Medicine最新文献

{"title":"Gut-brain axis: beneficial impact of Shouchella clausii spores on fructose induced dysfunction is associated with modulation of the deoxycholic acid - TGR5 pathway.","authors":"Maria Stefania Spagnuolo, Natasha Petecca, Francesca De Palma, Antonio Dario Troise, Angela Di Porzio, Valentina Barrella, Anella Saggese, Sabrina De Pascale, Marina De Stefano, Andrea Scaloni, Loredana Baccigalupi, Ezio Ricca, Susanna Iossa, Arianna Mazzoli, Luisa Cigliano","doi":"10.1186/s10020-026-01479-4","DOIUrl":"https://doi.org/10.1186/s10020-026-01479-4","url":null,"abstract":"<p><strong>Objective: </strong>The increased intake of added sweeteners, such as high-fructose corn syrup, has been associated with a rise in metabolic dysfunctions in gut and brain. While different evidence showed that dietary fructose induces gut microbiota reshaping, the sugar impact on specific bacteria-derived metabolites remains an understudied topic. In this study, we identified secondary bile acids (sBAs) as molecules differentially represented in plasma of rats fed a fructose-rich diet compared to control animals, and hypothesized that these metabolites might be a target for probiotic-based strategies to counteract sugar-induced metabolic disorders. To this aim, we investigated whether probiotic spores of Shouchella clausii SF174 ameliorate fructose-induced cognitive and metabolic dysfunctions and prevent molecular alterations in hippocampus and frontal cortex.</p><p><strong>Methods: </strong>Wistar rats were fed a fructose-rich diet, alone or in combination with the daily administration of Shouchella clausii spores, for six weeks. At the end of treatment, behavioral, metabolomic and molecular analyses were performed.</p><p><strong>Results: </strong>The probiotic spores exerted a protective effect on the memory function of fructose fed rats and prevented the decrease of markers of synaptic plasticity. This was associated with the maintenance of plasma and brain levels of the sBA deoxycholic acid and of its specific receptor Takeda G protein-coupled receptor 5. Further, spores beneficial modulation of fructose-induced peripheral and central inflammation was observed. Also, probiotic spores produced reshaping of the gut microbiota towards a composition exerting neuroprotective and anti-inflammatory effects.</p><p><strong>Conclusion: </strong>These results suggest that sBAs might act as a communication bridge along the microbiota gut-brain axis and suggest that their modulation, through probiotic administration, represents an effective strategy to counteract fructose-induced neuroinflammation and gut-brain dysfunction.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147864279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic and degradomic signatures of extracellular matrix remodeling in calcific aortic valve stenosis.","authors":"Ilaria Iacobucci, Vittoria Monaco, Alessia Lubrano Lobianco, Brunella Cipolletta, Leila Birolo, Maddalena Conte, Veronika A Myasoedova, Vincenza Valerio, Paolo Poggio, Valentina Parisi, Maria Monti","doi":"10.1186/s10020-026-01499-0","DOIUrl":"https://doi.org/10.1186/s10020-026-01499-0","url":null,"abstract":"<p><strong>Background: </strong>Aortic stenosis is a progressive fibro-inflammatory valvular disorder with major clinical burden and no disease-modifying pharmacological therapy. Defining molecular circuits associated with thrombo-inflammatory activation to extracellular matrix remodeling may enable future therapeutic targeting and biomarker development.</p><p><strong>Methods: </strong>Human aortic valves explanted from patients with severe aortic stenosis and non-stenotic surgical controls (aortic regurgitation) were profiled using a multi-layer mass spectrometry strategy. Global protein changes were quantified by label-free proteomics (data-independent acquisition). Extracellular matrix proteolysis was interrogated using an extracellular matrix-focused semi-tryptic peptide workflow. Collagen qualitative remodeling was assessed by mapping hydroxyproline enrichment. Differential abundance was evaluated using multiple-testing correction (false discovery rate). Selected candidates were validated by targeted multiple reaction monitoring, and elastin integrity was assessed histologically.</p><p><strong>Results: </strong>We identified 594 significantly modulated proteins in severe aortic stenosis, with predominant upregulation of complement/coagulation and extracellular matrix-related pathways. Targeted Multiple Reaction Monitoring confirmed key thrombo-inflammatory and matrix-associated candidates. Semi-tryptic profiling revealed a focused extracellular matrix degradomic signature dominated by small leucine-rich proteoglycans (decorin, lumican, PRELP), fibrillin-1, and collagen VI, consistent with preferential proteolytic targeting of structural matrix scaffolds. Histology showed marked elastin fragmentation in stenotic leaflets. Collagen post-translational modification analysis revealed increased hydroxyproline- bearing peptides across selected collagen chains despite minimal changes in total collagen abundance, indicating qualitative remodeling beyond protein accumulation.</p><p><strong>Conclusions: </strong>An integrated proteomic-degradomic-post-translational modification framework reveals concomitant thrombo-inflammatory activation to matrix breakdown and qualitative collagen remodeling in severe aortic stenosis, highlighting molecular circuits that may inform future biomarker development and therapeutic target discovery.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of the adhesion GPCR ADGRL4/ELTD1 as a novel potential prognostic biomarker for cerebral cavernous malformation disease.","authors":"Andrea Perrelli, Ashraqat Ahmed, Anna Onisiforou, Gwenola Boulday, Juan Zalvide, Celia M Pombo, José E Martínez, Alessio Paolini, Salim Abdelilah-Seyfried, Ioannis Petrakakis, Wolfram S Kunz, Robert Geffers, Christian Hartmann, Walter Bini, Gerasimos Baltsavias, Amir Samii, Helmut Bertalanffy, Saverio F Retta, Angela J Glading, Souvik Kar","doi":"10.1186/s10020-026-01495-4","DOIUrl":"https://doi.org/10.1186/s10020-026-01495-4","url":null,"abstract":"<p><strong>Background: </strong>Cerebral cavernous malformations (CCM) are angiographically occult vascular anomalies of the brain, characterized by dilated capillaries, increased vascular permeability, and loss of endothelial junctional protein complexes. Loss-of-function mutations in one of the three genes, namely KRIT1/CCM1, CCM2, and PDCD10/CCM3, have been associated with the disease pathogenesis, although the contribution of other genetic determinants besides CCM genes has been recently identified. Despite recent advances in understanding the molecular mechanism of the disease, the current lack of therapies and its unpredictable clinical behavior represent a significant challenge in the identification of diagnostic biomarkers. ADGRL4/ETLD1 (epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1), a G-protein coupled receptor (GPCR) protein is a known biomarker of angiogenesis and inflammation, and it has been suggested to be a key therapeutic target for stroke and high-grade gliomas. However, the relevance of ELTD1 in CCM pathogenesis remains unexplored.</p><p><strong>Methods: </strong>Through different analyses, including whole RNA transcriptome, immunohistochemistry, and real-time PCR, conducted in human CCM patients, cellular and animal models, herein we show the association between CCM disease and ELTD1.</p><p><strong>Results: </strong>The whole RNA transcriptome approaches demonstrated ELTD1 is differentially expressed, and gene expression analysis revealed it is significantly upregulated in surgically resected tissue and plasma samples from CCMs, and clinical correlation analysis showed that increased ELTD1 associates with the presence of Focal Neurological Deficits in patients. Immuno-expression showed a strong ELTD1 immunoreactivity in endothelial cells lining affected lesions. According to these elevated levels of ELTD1 in human patients, we also showed a robust increase in the expression level of ELTD1 in cellular and animal models of CCM disease.</p><p><strong>Conclusions: </strong>Taken together, our results demonstrate for the first time ELTD1 involvement in CCM pathogenesis, and its tight link with CCM genes. Thanks to this putative new prognostic biomarker, future clinical studies in larger patient cohorts will aim at improving the CCM disease management and risk stratification in patients, as well as placing the basis for targeted therapeutic strategies in CCM.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An ERRα-ZEB1 transcriptional signature predicts survival in triple-negative breast cancers.","authors":"Jing-Ru Shi, Coralie Poulard, Catherine Cerutti, Olivier Trédan, Muriel Le Romancer, Tie-Liu Shi, Jean-Marc Vanacker","doi":"10.1186/s10020-026-01487-4","DOIUrl":"https://doi.org/10.1186/s10020-026-01487-4","url":null,"abstract":"<p><strong>Background: </strong>Transcription factors (TFs) act together with co-regulators to modulate the expression of their target genes, which eventually dictates their pathophysiological effects. Depending on the co-regulator, TFs can exert different activities. The Estrogen Related Receptor α (ERRα) acts as a transcription factor that regulates several pathophysiological phenomena. In particular, interactions with PGC-1 co-activators are responsible for the metabolic activities of ERRα. In breast cancers however, ERRα exerts several tumor-promoting, metabolism-unrelated activities that do not depend on PGC-1, questioning the identity of the co-activators involved in these cancer-related effects.</p><p><strong>Methods: </strong>Bio-computing methods were used to identify a potential ERRα coactivating factor in aggressive breast cancers. Bench experiments (qPCR, ChIP, proximity ligation assays) were used to validate the effect of the co-factor on ERRα transcriptional activity specifically in triple negative breast cancer (TNBC) cells. Predictive value of ERRα-co-factor target genes on the survival of TNBC patients was studied.</p><p><strong>Results: </strong>ZEB1 appears as a major ERRα co-factor, involved in increased expression of direct ERRα targets that induce cell migration in TNBCs. Experimental validations establish that ERRα and ZEB1 interact together and are bound to the promoters of the target genes that they transcriptionally coregulate. Further analyses show that the ERRα-ZEB1 downstream transcriptional signature can predict the survival of TNBC patients.</p><p><strong>Conclusions: </strong>Our approach combining bio-computing as well as experimental validation allows to propose a gene signature, the high expression of which predicts TNBC patient survival. Down modulation of these genes could be promising against TNBCs.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitric oxide supplementation during extracorporeal resuscitation drives oxidative-inflammatory signaling and metabolic suppression in the post-cardiac arrest heart.","authors":"Abou Bakr M Salama, Daniele Linardi, Romel Mani, Maddalena Tessari, Qinghui Ou, Yasmin Y Salem, Ahmed Abdulsaboor, Ahmed M Shaker, Ahmad Gebreil, Ahmed Elbakri, Riham R E Abouleisa, Bahaael El Sady, Giovanni B Luciani","doi":"10.1186/s10020-026-01468-7","DOIUrl":"https://doi.org/10.1186/s10020-026-01468-7","url":null,"abstract":"<p><strong>Background: </strong>Myocardial dysfunction is a major determinant of mortality after cardiac arrest, yet the molecular events driving post-resuscitation injury remain incompletely understood. Nitric oxide (NO) has been proposed as a cardioprotective adjunct during extracorporeal life support (ECLS), but its mechanistic impact on myocardial recovery is unclear. We investigated whether NO supplementation during ECLS modulates oxidative stress, metabolic pathways, and apoptotic signaling in the post-cardiac arrest heart.</p><p><strong>Methods: </strong>Male Sprague Dawley rats underwent hypothermic cardiac arrest followed by ECLS resuscitation with or without NO supplementation (20 ppm). Myocardial tissue was analyzed using bulk RNA sequencing, quantitative RT-PCR, oxidative stress assays (MDA, 3-nitrotyrosine, total oxidant/antioxidant status), and TUNEL staining to characterize pathway-level alterations.</p><p><strong>Results: </strong>NO supplementation markedly increased cardiomyocyte apoptosis (46%±3 vs. 27%±2; p < 0.0001). Transcriptomic profiling revealed > 550 differentially expressed genes, highlighting upregulation of inflammatory and apoptotic cascades (MAPK, TNF, NF-κB, proteasome/TLR pathways) and profound suppression of metabolic programs essential for myocardial recovery, including fatty acid oxidation, branched-chain amino acid metabolism, and oxidative phosphorylation. NO induced a striking oxidative-nitrosative imbalance, with elevated MDA, 3-nitrotyrosine, and total oxidant status and reduced total antioxidant capacity, resulting in a threefold increase in the oxidative stress index.</p><p><strong>Conclusions: </strong>NO administration during ECLS drives a coordinated oxidative-inflammatory-apoptotic response and disrupts metabolic pathways necessary for myocardial recovery, suggesting a mechanistic basis for worsened post-arrest myocardial injury. These findings have direct implications for optimizing resuscitation strategies in human ECLS and may inform future therapeutic modulation of NO signaling.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic and microRNA-mediated regulation of pulmonary fibrosis and immune dysregulation in fatal COVID-19.","authors":"Gabriela Casani Cardoso, Regiane Stafim da Cunha, Guilherme Miniskiskosky, Cleber Machado-Souza, Lucia de Noronha, Caroline Busatta Vaz de Paula, Felipe Francisco Tuon, Edneia Amancio de Souza Ramos Cavalieri","doi":"10.1186/s10020-026-01467-8","DOIUrl":"https://doi.org/10.1186/s10020-026-01467-8","url":null,"abstract":"<p><strong>Background: </strong>Severe cases of COVID-19 can result in acute respiratory distress syndrome, extensive lung damage, and long-term structural changes, particularly extracellular matrix (ECM) remodeling. ECM remodeling is characterized by excessive collagen deposition and imbalanced activity of enzymes, such as matrix metalloproteinases. Although immune and inflammatory pathways in patients with COVID-19 are well understood, the epigenetic and post-transcriptional regulation is not well understood. In this exploratory study, we examined DNA methylation and miRNA-mediated regulation in lung tissues from fatal cases of COVID-19.</p><p><strong>Methods: </strong>Methods included gene and protein expression analyses, DNA methylation assays, evaluation of DNMT activity, MSP‒dPCR, miRNA profiling and pathway enrichment analysis.</p><p><strong>Results: </strong>We observed altered expression of ECM regulators, such as MMP2, MMP9 and ADAM33, as well as molecules related to SARS-CoV-2 infection, including ADAM17 and ACE2. Evidence of methylation-mediated regulation was observed for ADAM33 and ACE2. Two miRNAs were significantly downregulated (miR-16-5p and miR-30d-5p), whereas miR-19a-3p/19b-3p and miR-21-5p were upregulated. Pathway analysis revealed activation of p53, apoptosis, and growth factor related pathways, as well as the suppression of vascular, interferon and T-cell activation signaling pathways.</p><p><strong>Conclusion: </strong>Overall, these findings suggest that, in this cohort of fatal COVID-19 cases, lung tissue exhibits features consistent with ECM remodeling, epithelial fibrosis, and immune dysregulation. Additionally, the results raise the possibility that epigenetic alterations and miRNA-mediated regulatory mechanisms may be associated with disease progression in severe cases.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding GPCR signaling reprogramming in cancer: molecular mechanisms and therapeutic implications.","authors":"Shorouk Aldeyarbi, Marwan El-Deyarbi, Ashraf A Hussein, Zelal S Adi, Salahdein Aburuz","doi":"10.1186/s10020-026-01491-8","DOIUrl":"https://doi.org/10.1186/s10020-026-01491-8","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) constitute the largest membrane receptor family in the human genome and serve as key regulators of cell signaling, homeostasis, and pharmacologic response. Beyond their classical role in mediating extracellular stimuli through G-protein-dependent and independent pathways, which have a pivotal role of GPCR-mediated signaling pathways, including the cAMP-PKA/EPAC, IP3/PLC, PI3K/Akt/mTOR, and ERK/MAPK cascades, in driving oncogenic proliferation, apoptosis resistance, and metastasis. Furthermore, GPCRs are implicated in tumorigenesis through diverse molecular mechanisms, in which GPCR dysregulation contributes to cancer initiation and progression via aberrations at multiple genomic and regulatory levels, including copy number variations (CNVs), epigenetic modifications, post-transcriptional, and post-translational modifications. Despite their extensive biological roles and druggability, targeting GPCRs in cancer therapy has yielded promising outcomes, notably via SMO and chemokine receptor inhibitors. Overall, we aim to bridge the gap between fundamental GPCR signaling biology and clinical oncology. We integrated the deregulated expression and pathways of GPCR oncogenic processes, with the potential to be actionable biomarkers for tumor screening and clinical practices using GPCR drugable targets. Therefore, we represent and highlight pathway-specific signaling pathways with their tumor microenvironment interactions, drug combination strategies, and molecular imaging and theranostics applied in clinical practice and precision medicine.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EndMT in vascular cognitive impairment and dementia: mechanisms, evidence gaps, and therapeutic opportunities.","authors":"Juhyun Song","doi":"10.1186/s10020-026-01500-w","DOIUrl":"https://doi.org/10.1186/s10020-026-01500-w","url":null,"abstract":"<p><p>Vascular cognitive impairment and dementia (VCID) is increasingly recognized as a consequence of chronic cerebrovascular dysfunction, including cerebral small vessel disease and clinically defined entities such as post-stroke cognitive impairment (PSCI). Clinical and experimental studies indicate that endothelial injury and maladaptive microvascular remodeling can precede cognitive decline through cerebral blood flow dysregulation, impaired neurovascular coupling, and blood-brain barrier (BBB) disruption, with downstream neuroinflammatory amplification. A recurring feature across these settings is redox imbalance: reactive oxygen species (ROS) derived from mitochondria, NADPH oxidases, and uncoupled endothelial nitric oxide synthase act not only as mediators of oxidative injury but also as compartmentalized signaling cues that remodel endothelial transcriptional and epigenetic states. Here, I review how redox-sensitive modules-including TGF-β/Smad, NF-κB, HIF-1α, Wnt/β-catenin, and Notch signaling, together with chromatin regulation and non-coding RNAs-may initiate or stabilize endothelial-to-mesenchymal transition (EndMT) and partial EndMT-like programs during chronic vascular stress. I then discuss how EndMT-like reprogramming could contribute to BBB fragility, extracellular matrix remodeling, vascular stiffening, hypoperfusion, and neurovascular dysfunction, while highlighting priorities for in vivo causal testing and potential reversibility of partial EndMT. Finally, I map key mechanistic nodes to potential therapeutic classes to inform precision strategies targeting putative pathogenic redox-EndMT circuits rather than global oxidative stress.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Context-dependent release of HMGB1: cell death mode, cell type and LPS stress drive monomer and heterocomplex formation.","authors":"Harini Pechiappan, Rebecka Heinbäck, Sigrid Stråtveit Gravning, Kjerstin Jakobsen, Richard Davies, Cecilia Aulin, Helena Erlandsson Harris","doi":"10.1186/s10020-026-01489-2","DOIUrl":"https://doi.org/10.1186/s10020-026-01489-2","url":null,"abstract":"<p><strong>Background: </strong>HMGB1 acts as an alarmin when released from stressed or dying cells. In vitro, HMGB1 has previously been demonstrated to readily form complexes with other molecules and through intermolecular disulfide bond formation form homodimers. Recently, dimerized HMGB1 was identified in serum of LPS-challenged mice. In cancer, HMGB1 has been described as having both tumour-promoting and tumour-suppressing features, possibly dependent on the form of HMGB1 released into the tumour microenvironment. Factors determining the form in which HMGB1 is released remain, however, largely unexplored. We therefore investigated the form of HMGB1 released during different cell death modes and in response to LPS stress using various tumour cell lines.</p><p><strong>Methods: </strong>Supernatants were collected from ten non- and LPS-treated tumour cell lines and necrotic, apoptotic and pyroptotic THP-1 monocytic cells, to assess active and passive secretion of HMGB1. Released proteins were concentrated by TCA-precipitation and analysed by Western blotting under reducing and non-reducing conditions to detect monomeric, dimeric, or HMGB1-protein complexes. Co-immunoprecipitation and LC-MS/MS were used to identify binding partners of extracellular HMGB1.</p><p><strong>Results: </strong>Tumour cells were found to release monomeric HMGB1 and HMGB1 heterocomplexes in the 50-60 kDa range, as indicated by their persistent high molecular weight under reducing conditions. Furthermore, we identified that HMGB1 interacts with ribosomal proteins, histone H2B, and SRP9 following LPS treatment of microglial SIM-A9 cells.</p><p><strong>Conclusions: </strong>HMGB1 readily formed heterocomplexes, but not homodimers in vitro across multiple cell lines, with differences between LPS-treated and untreated conditions. The form of released HMGB1 was influenced by cell type, cell death mode, and LPS stress.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LARS promotes hepatocellular carcinoma progression via the PI3K/AKT/mTOR pathway and interaction with RPS5, and serves as a prognostic biomarker.","authors":"Hanbin Chen, Wei Chen, Shicheng Xie, Bin Wang, Shishi Zhu, Athanasios G Papavassiliou, Zhijie Yu, Jinglin Xia","doi":"10.1186/s10020-026-01490-9","DOIUrl":"https://doi.org/10.1186/s10020-026-01490-9","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) caused many cancer deaths around the world. Its progression involves complex mechanisms, creating an urgent need to identify new therapeutic targets. Leucine-tRNA synthetase (LARS) is a key enzyme for protein synthesis, but its specific role and mechanism in HCC are not well understood.</p><p><strong>Purpose: </strong>This research aims to investigate the biological function, molecular mechanism, and clinical relevance of the LARS gene in HCC progression, to assess its potential as a treatment target.</p><p><strong>Methods: </strong>LARS expression was assessed in HCC cell lines (PLC-PRF-5, HCC-LM3) and in mouse subcutaneous tumor models using siRNA and adeno-associated virus (AAV). Techniques including Cell Counting Kit-8(CCK-8), colony formation, EdU, Transwell, wound healing, and flow cytometry were used to measure cell proliferation, migration, invasion, and apoptosis. RNA-seq, proteomics (TMT), western blot, co-immunoprecipitation (Co-IP) with mass spectrometry, molecular docking, and molecular dynamics simulation were employed to study the affected signaling pathway (PI3K/AKT/mTOR) and interacting protein (RPS5). The TCGA (The Cancer Genome Atlas) database and UALCAN platform were used to analyze links between LARS expression and clinicopathological features or prognosis in HCC patients.</p><p><strong>Results: </strong>Reducing LARS expression significantly inhibited the proliferation, colony formation, migration, and invasion of HCC cells, while promoting apoptosis. In mice, LARS knockdown markedly slowed tumor growth. Mechanistic studies showed that reducing LARS expression levels affected the PI3K/AKT/mTOR signaling pathway and led to decreased levels of the key interacting protein RPS5. Overexpressing RPS5 partly reversed the proliferation inhibition caused by LARS depletion. Molecular docking and dynamics simulations suggested that the environmental contaminant triphenyl phosphate (TPP) might bind to the LARS protein. Clinical data analysis revealed that LARS expression is higher in HCC tissues. High LARS expression was significantly associated with shorter overall survival (OS) in patients and correlated positively with various clinical features like tumor stage, grade, and TP53 mutation status.</p><p><strong>Conclusion: </strong>LARS helped HCC become worse by affecting the PI3K/AKT/mTOR pathway and working with RPS5. High LARS meant a worse outcome for patients. This suggested LARS could be used to predict disease or as a treatment target in HCC.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}