Molecular Medicine最新文献

{"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}

{"title":"Deficiency of Setd2 in mesenchymal stem cells facilitates the progression of myelodysplastic syndrome to leukemia.","authors":"Rou-Jia Wang, Zi-Juan Li, Bing-Yi Chen, Juan Guo, Ying Tao, Hong-Ping Li, Ming-Yue Fei, Bin-He Chang, Mu-Ying Zhao, Lei Shi, Si-Da Zhao, Zheng Zhang, Ji-Ying Su, Lu-Xi Song, Qi He, Dong Wu, Ling-Yun Wu, Jia-Ying Zhang, Li-Juan Zong, Xiao-Jian Sun, You-Shan Zhao, Lan Wang, Chun-Kang Chang","doi":"10.1186/s10020-026-01492-7","DOIUrl":"https://doi.org/10.1186/s10020-026-01492-7","url":null,"abstract":"<p><p>While previous studies have indicated that H3K36me3, which is mediated by Setd2, may regulate the cell fate of mesenchymal stem cells (MSCs) both in vitro and in vivo, the specific role of MSCs in the onset and progression of MDS remains unclear. Thus, the histone methyltransferase Setd2 is implicated in MDS-associated leukemia. This study utilized NUP98-HOXD13 (NHD13) mice with targeted deletion of Setd2 in MSCs. Here, we found that Setd2-deficient mice undergo faster leukemia transformation than control mice do, as evidenced by the abnormal differentiation of hematopoietic stem progenitor cells in the bone marrow, abnormal hematopoiesis, and increased number of blast cells. Compared with that of control mice, the morphology of NHD13 mouse MSCs with Setd2 deficiency was irregular, and the support function of hematopoietic cells was compromised. This study demonstrated that targeted deletion of Setd2 in MSCs facilitates the advancement of MDS. Furthermore, we identified increased expression of coagulation factor XII as a key leukemic transformation mediator in Setd2-deficient MSCs. Moreover, we found that SETD2 expression is significantly lower in high-risk MDS patients than in low-risk MDS patients, further suggesting that the targeted deletion of Setd2 in MSCs is associated with MDS progression. Collectively, our results suggest that Setd2 in MSCs suppresses MDS progression to leukemia through coagulation factor XII-mediated suppression of the stem cell support capacity of MSCs. Overall, this study sheds light on the pathogenesis of MDS and provides a therapeutic strategy for regulating the microenvironment in patients with MDS who cannot be cured by haematopoietic stem cell transplantation.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817618","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":"Single-cell analysis reveals cellular heterogeneity and limits of marker-based assessment in retinal ganglion cell-enriched organoid cultures.","authors":"Jessica Yuen Wuen Ma, Dulce B Vargas-Landin, Janya Grainok, Alice Pébay","doi":"10.1186/s10020-026-01488-3","DOIUrl":"https://doi.org/10.1186/s10020-026-01488-3","url":null,"abstract":"<p><p>Human pluripotent stem cell (hPSC)-derived retinal organoids provide an in vitro system for generating retinal ganglion cells (RGCs), yet the cellular composition and developmental fidelity of RGC-enriched cultures remain insufficiently characterised. Here, we tested an RGC-enriched approach involving dissociation of hPSC-derived retinal organoids at day 40, corresponding to peak expression of RGC markers, followed by two-dimensional culture conditions intended to enrich for RGC survival. Flow cytometry was used to assess the expression of RGC markers, including POU4F, ISL1, SNCG, and THY1. Across four samples, POU4F expression ranged from 79-95%, ISL1 from 18-58%, SNCG from 22-91% and THY1 from 3-29%, indicating substantial variability between markers and samples. Single-cell RNA sequencing analysis of 73,642 cells identified multiple retinal lineages, including retinal progenitors, RGCs, photoreceptor-committed cells, amacrine and horizontal cells, and retinal pigment epithelium (RPE), as well as off-target populations comprising HOX-enriched posterior neural cells and other cell types. Cellular composition varied across samples. Transcriptomically defined RGCs accounted for 19-45% of cells across samples, with different RGC subclusters identified. These findings indicate that marker-based assessments alone may overestimate RGC identity and reveal substantial cellular heterogeneity, including partially specified RGC states and off-target populations. Accordingly, the term \"RGC-enriched\" is used in a relative sense based on comparison with previously published scRNA-seq-validated differentiation studies rather than indicating complete lineage purity. Interpretation of RGC enrichment should consider differences between protein- and transcript-based measurements, sampling variability between assays, and the incomplete specification of functional RGC subtypes.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817624","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":"Divergent myeloid and lymphoid immune landscapes in HPV/p16 positive and HPV/p16 negative oropharyngeal squamous cell carcinomas and their lymph node metastases.","authors":"Raphaela Graessle, Iris Piwonski, Achim Franzen, Heidi Olze, Anja A Kühl, Michael Hummel, Ulrike Erben, Annekatrin Coordes","doi":"10.1186/s10020-026-01481-w","DOIUrl":"10.1186/s10020-026-01481-w","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13130499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbiota-derived metabolites and cardiovascular implications in Inflammatory Bowel Disease (IBD).","authors":"Ivna Olić, Nikola Pavlović, Marko Kumrić, Roko Šantić, Andre Bratanić, Joško Božić","doi":"10.1186/s10020-026-01493-6","DOIUrl":"https://doi.org/10.1186/s10020-026-01493-6","url":null,"abstract":"<p><strong>Background: </strong>Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic relapsing systemic disorder associated with significant extraintestinal manifestations. Emerging evidence indicates that cardiovascular disease represents a clinically important comorbidity in IBD, driven by persistent low-grade inflammation, endothelial dysfunction, and metabolic disturbances.</p><p><strong>Main body: </strong>The gut microbiota, recognized as a key regulator of host metabolism and immune homeostasis, contributes to cardiovascular physiology through the production of bioactive metabolites. These microbiota-derived metabolites - including short-chain fatty acids, secondary bile acids, trimethylamine N-oxide, tryptophan-derived indoles, and polyphenol-derived compounds - can exert cardioprotective or cardiotoxic effects depending on their balance and bioavailability. In IBD, intestinal dysbiosis and impaired epithelial barrier integrity profoundly alter microbial metabolic output, thereby disrupting systemic inflammatory and cardiovascular pathways. This review summarizes current evidence on the role of microbiota-derived metabolites in cardioprotection and examines how IBD-associated dysbiosis disrupts these protective mechanisms.</p><p><strong>Conclusion: </strong>Understanding the interplay between gut dysbiosis and cardiovascular risk in IBD may open new therapeutic avenues. Targeting the gut microbiota and its metabolic output represents a promising strategy to mitigate cardiovascular risk in this patient population.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776411","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":"IL-6 triggers lysosomal degradation of LDL-R and enhances LDL-C uptake in vascular endothelial cells via macropinocytosis.","authors":"Mulugeta M Zegeye, Jishamol T Veettil, Geena V Paramel, Seta Kurt, Samira Salihovic, Liza U Ljungberg, Ashok K Kumawat, Allan Sirsjö","doi":"10.1186/s10020-026-01484-7","DOIUrl":"https://doi.org/10.1186/s10020-026-01484-7","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated in vitro and multi-cohort cross-omics analysis of HTLV-1-associated lung pathology reveals a RelA-dependent mechanism for monocyte recruitment and differentiation.","authors":"Clément J F Heymann, Mieke Gouwy, Robin Hermans, Jean-Claude Twizere, Tatiane Assone, Jorge Casseb, Isaac Racine, Isabelle Cleynen, Edward L Murphy, Roberta Bruhn, Dominique Schols, Evelien Vanderlinden, Johan Van Weyenbergh","doi":"10.1186/s10020-026-01482-9","DOIUrl":"https://doi.org/10.1186/s10020-026-01482-9","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776442","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":"Fludarabine disrupts the STAT1/AhR interaction to attenuate type 1 diabetes by inducing tolerogenic dendritic cells along with targeting effector T cells.","authors":"Shan-Jie Rong, Chun-Liang Yang, Ke Xiao, Qi-Jie Chen, Jia-Wei Zhao, Yue-Chen Liu, Yan-Chao Guo, Fa-Xi Wang, Xin Li, Xi Luo, Yang Li, Dan-Ni Song, Weikuan Gu, Xiang-Yun Zhu, Shi-Wei Liu, Ping Yang, Maryam S Al-Motawa, Omar Albagha, Fei Sun, Qi-Lin Yu, Ying Yao, Tian-Tian Yue, Cong-Yi Wang","doi":"10.1186/s10020-026-01483-8","DOIUrl":"https://doi.org/10.1186/s10020-026-01483-8","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776369","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":"Impact of oxygen-ozone mixture on cellular functions: a biochemical perspective across cell types.","authors":"Ayesha Khalid, Alessandra Sala, Antonella Forlino, Roberta Besio","doi":"10.1186/s10020-026-01475-8","DOIUrl":"https://doi.org/10.1186/s10020-026-01475-8","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147691103","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":"Genetic epidemiology of C9orf72 repeat expansion associated amyotrophic lateral sclerosis in Hungary.","authors":"Zsófia Flóra Nagy, Adrienn Géresi, Zoltán Grosz, Barbara Trombitás, Margit Pál, Dominika Nagy, András Salamon, Péter Balicza, Lívia Dézsi, Péter Klivényi, Márta Széll, Mária Judit Molnár","doi":"10.1186/s10020-026-01465-w","DOIUrl":"https://doi.org/10.1186/s10020-026-01465-w","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. The most common genetic cause of ALS is the hexanucleotide repeat expansion in the C9orf72 gene, which is associated with earlier disease onset, faster progression, and an increased frequency of cognitive and psychiatric involvement. Data on population-specific characteristics of C9orf72-associated ALS remains limited in Central and Eastern Europe.</p><p><strong>Methods: </strong>Between 2011 and 2024, a total of 959 ALS patients fulfilling established diagnostic criteria were screened for C9orf72 repeat expansions at two Hungarian centers. Hexanucleotide repeat expansions were analyzed using repeat-primed long-read PCR. Repeat numbers exceeding 30 were considered pathogenic. Clinical, demographic, and disease course data were retrospectively collected and analyzed.</p><p><strong>Results: </strong>Pathogenic C9orf72 repeat expansions were identified in 63 of 959 patients, corresponding to a prevalence of 6.57% among Hungarian ALS patients. Bulbar onset was the most common presentation and was associated with faster progression and shorter survival (mean survival: 27.8 months). Cognitive impairment and psychiatric comorbidities were present in a substantial proportion of patients and were associated with slower functional decline. Regional differences in survival were observed, likely reflecting disparities in healthcare access rather than biological factors.</p><p><strong>Conclusions: </strong>This study provides the first comprehensive national characterization of C9orf72 repeat expansion-associated ALS in Hungary, based on a genetically defined cohort assembled over 13 years. Despite limitations related to retrospective data collection and cohort size, this ethnically homogeneous dataset offers valuable insight into population-specific clinical and epidemiological features and complements larger international studies. Systematic characterization and longitudinal follow-up of genetically defined, trial-ready ALS cohorts will be essential as targeted therapies for C9orf72-associated ALS approach clinical implementation.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147691105","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}