Molecular Medicine最新文献

{"title":"Thyroid hormones and hearing loss.","authors":"Yuxin Deng, Junzhe Dong, Haiyan Cao, Huamao Cheng, Sen Chen","doi":"10.1186/s10020-026-01569-3","DOIUrl":"https://doi.org/10.1186/s10020-026-01569-3","url":null,"abstract":"<p><p>Hearing loss is a growing global public health issue. Major causes of deafness include infection, genetic mutations, ototoxic drug exposure, aging and endocrine disorders. Thyroid hormone plays a critical role in the development and maturation of the mammalian auditory system. Thyroid dysfunction, the most common endocrine abnormality, frequently leads to hearing impairment. Nevertheless, this thyroid-related deafness is often underrecognized in both patients and clinicians. Previous studies have indicated that thyroid hormone regulates the development of the organ of Corti, the greater epithelial ridge, the stria vascularis, and peripheral auditory neurons. Congenital thyroid dysfunction often results in hearing loss by hindering inner ear development. Acquired thyroid dysfunction can increase the incidence of deafness. Currently, most studies support the efficacy of thyroid hormone replacement therapy for hypothyroidism-related deafness, establishing it as a promising approach. However, treatment for hyperthyroidism-related deafness remains under investigation. This review focuses on the relationship between thyroid dysfunction and hearing loss. The clinical audiological characteristics, pathophysiological mechanisms, and typical pathological manifestations of thyroid-related hearing loss are summarized. And thyroid hormone replacement therapy is concluded. This will help provide new insights and research directions for the precise prevention and treatment of hearing loss associated with thyroid dysfunction.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520294","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":"O-GlcNAcylation: the metabolic-immune translator in tumor evolution and treatment.","authors":"Jinwen Zhao, Jincai Lv, Huanhuan Wang, Zhuangzhuang Zheng, Ying Xin, Xin Jiang","doi":"10.1186/s10020-026-01573-7","DOIUrl":"10.1186/s10020-026-01573-7","url":null,"abstract":"<p><p>O-GlcNAcylation is a dynamic post-translational modification of serine/threonine residues in proteins that modulates cellular activities by influencing the function of protein substrates, including their cellular localization, stability, and protein-protein interactions. The hexosamine biosynthesis pathway (HBP) utilizes various metabolites to synthesize uridine diphosphate N-acetylglucosamine, which serves as the substrate for O-GlcNAcylation. Metabolic reprogramming of tumors modulates HBP flux, thereby influencing O-GlcNAcylation levels. O-GlcNAcylation plays a pivotal role in regulating immune signaling pathways and their targets. Consequently, O-GlcNAcylation may act as a central node linking metabolic reprogramming and immune evasion. In this review, we summarize the current progress in understanding the role of O-GlcNAcylation in immunometabolism and explore how O-GlcNAcylation serves as a metabolic-immune translator that regulates tumor progression and therapeutic responses. Furthermore, we discuss the potential of O-GlcNAcylation as a therapeutic target, providing a promising new approach for cancer treatment.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148536502","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":"OGT as a metabolic-epigenetic integrator in cancer: context-dependent mechanisms and therapeutic vulnerabilities.","authors":"Marissa El Hajje, Gustavo Henrique Goulart Trossini","doi":"10.1186/s10020-026-01563-9","DOIUrl":"10.1186/s10020-026-01563-9","url":null,"abstract":"<p><strong>Background: </strong>Accumulating evidence shows that specific dietary elements and metabolic conditions significantly regulate gene expression through epigenetic processes. These observations link the etiology of metabolic disorders and cancer to nutrient-dependent epigenetic reprogramming. In this context, O-GlcNAc transferase (OGT) functions as a context-dependent nutrient sensor and metabolic-epigenetic integrator.</p><p><strong>Main text: </strong>This enzyme participates in the \"histone code\" by regulating gene expression and modulating chromatin remodeling. In Drosophila melanogaster, OGT is a bona fide Polycomb group (PcG) protein; however, in mammals it functions as a context-dependent, non-canonical modulator of PRC2 activity rather than a canonical PcG member. OGT interacts with Ten-Eleven Translocation (TET) family proteins, which are involved in DNA hydroxylation. This suggests that O-GlcNAcylation serves as a critical bridge between dietary influences and epigenetic regulation. Evidence from animal models supports a significant role for OGT in polycomb-dependent gene silencing. Notably, OGT modifies all core histones and may constitute a vital component of the histone code. Aberrant O-GlcNAcylation of signaling proteins, metabolic enzymes, and transcriptional regulators can drive oncogenesis by dysregulating cellular proliferation, survival, and metabolic reprogramming. However, the effects of O-GlcNAcylation are not uniformly pro-oncogenic; context-dependent, tumor-suppressive, and protective functions have also been reported, underscoring the need for nuanced, cancer type-specific interpretation. OGT interacts with diverse epigenetic factors including HCF-1, TET, mSin3A, HDAC, and BAP1, linking the cellular metabolic state to the epigenetic profile of cancer cells.</p><p><strong>Conclusions: </strong>In this review, we critically evaluate OGT's role in cancer epigenetics within a metabolism-epigenetics-signaling crosstalk framework, and discuss OGT inhibitor development and the challenges of therapeutic translation, including selectivity and bioavailability.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148497745","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":"Serum meprin α levels for the detection of systemic inflammatory response syndrome.","authors":"Silje Beckinger, Marion Mengel, Matthias Lindner, Vasco Köhling, Florian Peters, Inez Götting, Johanna Stoske, Jannik Rusch, David I Radke, Dirk Schädler, Cynthia Bülck, Kira Bickenbach, Malina Rüffer, Reiner K Mailer, Neele Schumacher, Thomas Renné, Michael Haase, Ronald Naumann, Christoph Becker-Pauly, Sascha Rüffer","doi":"10.1186/s10020-026-01570-w","DOIUrl":"10.1186/s10020-026-01570-w","url":null,"abstract":"<p><strong>Background: </strong>Systemic inflammatory response syndrome (SIRS) is a frequent critical condition in clinical patients marked by dysregulated immune activation and high mortality. Early initiation of appropriate interventions are important for patient outcome, but molecular markers for diagnosis are not SIRS-specific.</p><p><strong>Methods: </strong>We performed hematological analyses and health-status assessments on a transgenic disease mouse model that recapitulates elevated epidermal levels of the metalloprotease meprin α (K5Mα) reported in inflammatory skin diseases. In a cohort of intensive care patients that either developed SIRS (n = 19) or not (n = 29), we measured parameters associated with systemic inflammation and organ function as well as serum meprin α levels.</p><p><strong>Results: </strong>K5Mα mice developed fatal SIRS characterized by hypothermia, severe weight loss, hypochromic microcytic anemia, neutrophilic leukocytosis and cytokine release syndrome. Serum concentrations of meprin α correlated with disease progression in K5Mα mice. We detected high meprin α levels in the serum of intensive care patients who developed SIRS but in none of the patients who did not develop SIRS. Serum meprin α levels significantly correlated with clinical parameters like C-reactive protein, procalcitonin and white blood cell count, but unlike all other measured inflammatory parameters allowed a clear identification of SIRS patients.</p><p><strong>Conclusions: </strong>We propose serum meprin α levels as a potential biomarker for SIRS. However, we would like to emphasize that due to our limited cohort size subsequent larger-scale, multicentered studies are warranted to validate our findings and potentially provide more detailed insight into whether there is an association between elevated meprin α serum levels and specific causes of SIRS or dysfunction of particular organ systems.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13380840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148497790","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":"Secretory leukocyte protease inhibitor (SLPI) attenuates TLR4/NF-κB-mediated neuroinflammation in amyotrophic lateral sclerosis: a candidate molecule associated with neuro-pathology.","authors":"Ming-An Li, Yi-Zhi Song, Ting Li, Jian Wu, Yue Tao, Rui Hu, Chen-Meng Qiao, Chun Cui, Wei-Jiang Zhao, Yan-Qin Shen","doi":"10.1186/s10020-026-01572-8","DOIUrl":"10.1186/s10020-026-01572-8","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder driven by neuroinflammation involving activated microglia and astrocytes, which accelerates the loss of motor neurons. While Secretory leukocyte protease inhibitor (SLPI) is known for its immunomodulatory properties, its specific role in ALS pathogenesis has not been fully established. This study aimed to characterize the expression patterns and functional significance of SLPI in ALS models.</p><p><strong>Methods: </strong>The study utilized SOD1^G93A mice to analyze the spatiotemporal dynamics of SLPI expression in the gastrocnemius muscle, lumbar spinal cord, and serum across different disease stages. In vitro functional assays were conducted using siRNA-mediated knockdown of SLPI in BV2 (microglia), MA (astrocytes), and NSC-34 (motor neurons) cell lines. Additionally, recombinant SLPI protein was applied to LPS-stimulated BV2 cells to investigate its effect on the TLR4/ NF-κB signaling pathway.</p><p><strong>Results: </strong>In SOD1^G93A mice, SLPI was significantly upregulated in the gastrocnemius muscle from the pre-symptomatic stage (60 days) through the late stage (130 days). In the lumbar spinal cord, SLPI showed a transient initial increase but declined sharply by the end-stage; a similar significant reduction was observed in late-stage serum levels. In vitro, SLPI knockdown exacerbated pro-inflammatory cytokine production in all three cell types and impaired the antioxidant capacity of NSC-34 motor neurons. Mechanistically, recombinant SLPI attenuated inflammation in BV2 cells by modulating the TLR4/NF-κB pathway.</p><p><strong>Conclusions: </strong>The dynamic changes in SLPI levels suggest its potential relevance as a candidate molecule for disease staging. Meanwhile, its protective effects in regulating inflammation suggest that it could be a promising therapeutic candidate for mitigating ALS-associated neuroinflammation.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471892","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":"The dual role of RIPK family in IBD: from cell death to therapeutic targeting.","authors":"Lele Jiang, Along Gou, Anjuan Kang, Feixing Yan, Yujun Qiao, Fanxiang Xu, Yinliang Bai","doi":"10.1186/s10020-026-01556-8","DOIUrl":"10.1186/s10020-026-01556-8","url":null,"abstract":"<p><p>The receptor-interacting serine/threonine-protein kinase (RIPK) family, particularly RIPK1, RIPK2, and RIPK3, functions as a central regulatory hub at the intersection of cell death and inflammatory signaling, critically shaping the pathogenesis of inflammatory bowel disease (IBD). These kinases exhibit context-dependent dual roles in maintaining intestinal homeostasis and driving mucosal inflammation. RIPK1 operates as a molecular switch, with its scaffold activity sustaining epithelial survival via the NF-κB and MAPK pathways, whereas its kinase activity promotes apoptosis and necroptosis under pathological conditions. RIPK2 acts as an essential adaptor downstream of nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2), mediating antimicrobial host defense while contributing to excessive inflammation upon dysregulation. RIPK3, a core executor of necroptosis, also exerts kinase-independent immunomodulatory functions that influence tissue repair and inflammatory resolution. Dysregulation of RIPK signaling disrupts epithelial barrier integrity, amplifies inflammatory cascades, and engages in crosstalk with other programmed cell death modalities, such as pyroptosis, thereby exacerbating chronic intestinal injury. Therapeutic targeting of RIPK pathways has shown promise in preclinical models; however, achieving selective modulation that suppresses pathogenic signaling while preserving physiological functions remains a critical challenge. We propose that function-selective targeting of RIPKs, rather than complete inhibition, represents an essential direction for future IBD therapy.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148472021","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":"A multiomic investigation of human milk-derived extracellular vesicles in perinatal HIV and antiretroviral therapy exposure.","authors":"Allison Kupsco, Jennifer Jao, Landon Myer, Elaine J Abrams, Fang Wang, Jalean Dominguez, Allison Zerbe, Elton Mukonda, Hlengiwe P Madlala, Sandisiwe Matyesini, Daniel T Robinson, Yunping Qiu, Irwin J Kurland, Haotian Wu","doi":"10.1186/s10020-026-01567-5","DOIUrl":"10.1186/s10020-026-01567-5","url":null,"abstract":"<p><strong>Background: </strong>Human milk (HM) is beneficial for early infant development, and breastfeeding is recommended globally for women with HIV (WHIV) on antiretroviral therapy (ART). HM has a high extracellular vesicle (EV) content, and distinct HM fractions may be enriched for unique small metabolites, lipids, oxylipins, and microRNAs, which may differ by HIV/ART exposure. Our objective was to characterize the metabolomic and miRNA differences between milk fractions and in relation to HIV/ART.</p><p><strong>Methods: </strong>HM was collected at 6 weeks postpartum from WHIV receiving ART and HIV-seronegative women in South Africa (N = 20/group). Milk was fractionated into whole milk, skim milk, and EVs, which we isolated from skim milk using size-exclusion chromatography. Widely targeted small metabolite (~ 550 metabolites) and lipid profiling (~ 1500 lipid species in 24 + lipid classes) were measured with Ultra Performance Liquid Chromatography-Triple quadrapole Mass Spectrometry on whole milk, skim milk, and EVs. EV-miRNAs were sequenced on an Illumina NovaSeq. We used linear models to compare levels of lipids, metabolites, and miRNAs in HM EVs of WHIV versus HIV-seronegative women adjusting for covariates.</p><p><strong>Results: </strong>There were 658 lipids, 130 oxylipins, and 274 small metabolites detected across all HM fractions, with fewer compounds detected in HM EVs compared to whole and skim milk. HM EVs were enriched for fatty acid metabolism and metabolic products of linoleic acid (false discovery rate [FDR] p < 0.05). Triacylglycerols, TAG47:0 and TAG49:0, were lower in whole and skim milk of WHIV participants. Conversely, 18 small metabolites in HM EVs were associated with HIV status, but not in whole or skim milk. Of 187 detected EV-miRNAs, miR-148b-5p was significantly lower in WHIV, which was also validated by qPCR.</p><p><strong>Conclusions: </strong>These preliminary results suggest that EVs may better represent differences in milk metabolites from HIV/ART exposure than whole milk or skim milk. EV contents altered in WHIV may be relevant for lipid, vitamin and energy metabolism, and metabolic health. Future research is warranted to assess the relationship between HM EV contents and child health.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov-ID: NCT04991402.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471900","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":"Role of chromatin remodeling and immunopharmacology in cancer therapy.","authors":"Syeda Kiran Riaz, Mehwish Iqbal, Farwa Tahir, Tariq Iqbal, Faraz Ahmad, Muhammad Saboor, Asif Naseer, Shafiul Haque, Vaibhav Srivastava","doi":"10.1186/s10020-026-01557-7","DOIUrl":"10.1186/s10020-026-01557-7","url":null,"abstract":"<p><p>Epigenetic modifications play a crucial role in cancer, influencing cellular physiology, extracellular matrix (ECM) remodeling, and immune responses. With growing emphasis on chromatin remodeling and the epigenetic regulation of immunity, these regulatory pathways and related players have become focal points of oncological investigations. Epigenetic manipulation of immune system components has emerged as a promising strategy in cancer treatment. Several FDA-approved \"epi-drugs\" target the epigenome to modulate immune responses and offer new opportunities across different cancers. DNA repair pathways contribute significantly to the avoidance of cancer initiation and also contribute to cellular resistance in cancer treatment. Chromatin remodelers such as INO80, Fun30, and RAD54 play essential roles in DNA damage response (DDR) through homologous recombination and non-homologous end-joining pathways, and their dysregulation leads to genome instability and tumor progression. Chromatin remodeling complexes, including SWI/SNF and CHD families, are frequently altered across various cancer types, further highlighting their role in cancer pathophysiology. Targeting these chromatin modifiers and associated DNA repair mechanisms may provide novel therapeutic options. In addition, combining epigenetic modulators with immunotherapies has shown promise in enhancing responses to immune checkpoint blockade. Epigenetic drugs such as histone deacetylase (HDAC) inhibitors and DNA methylation inhibitors are being explored for their synergistic effects with immunotherapy. While the interplay between chromatin remodeling, DNA repair, and immune responses provides a strong framework for developing targeted oncological strategies, further research is required to better understand these interactions and optimize their clinical application.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456511","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":"Glycosylation modification: a trigger for obesity and its complications?","authors":"Changzan Wang, Wenying Yi, Xianghui Li, Xinyu Li, Meiying Wu, Wen Zhou, Maierhaba Maimaitiaili, Dilare Tuerhong, Nuerbiye Nuermaimaiti","doi":"10.1186/s10020-026-01565-7","DOIUrl":"10.1186/s10020-026-01565-7","url":null,"abstract":"<p><p>Obesity and its related metabolic diseases have increasingly become a significant public health challenge threatening the health of populations worldwide. The pathophysiological mechanisms contributing to the progression of obesity are intricate and diverse, highlighting the need for the creation of novel and effective intervention strategies aimed at the treatment of obesity and its associated metabolic diseases. An increasing number of studies indicate that glycosylation modifications play a crucial role in the onset and progression of obesity and its complications. Studies on glycosylation not only reveal its involvement in regulating the mechanisms of obesity and its complications but also provide new avenues for targeted therapies. Although significant advancements have been made in understanding the fundamental molecular mechanisms by which glycosylation modifications affect obesity and its related complications, many questions remain unanswered. For instance, through which specific sites does glycosylation regulate the occurrence of obesity and its complications? Furthermore, do glycosylation modifications interact with other post-translational modifications (PTMs) of proteins in the regulation of obesity and its complications? What are the specific pathways of O-linked β-N-acetylglucosamine (O-GlcNAc) signaling in obesity and its complications? This article summarizes recent research on the role of glycosylation in obesity and its complications, lists relevant specific glycosylation sites, and discusses the interactions between glycosylation modifications and other PTMs of proteins, providing new perspectives and insights for clinical treatment of obesity and its complications.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471906","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":"Single-cell transcriptomic profiling reveals PDK4 upregulation and impaired VEGF-C/VEGFR3 signaling in cardiac lymphatic endothelial cells in diabetic cardiomyopathy.","authors":"Yufeng Yan, Xunuo Wang, Congfei Zhu, Zihao Jiang, Jing Wang, Junjie He, Lei Xu, Xiaobin Zhou, Qing Ge, Zuoying Hu, Guangfeng Zuo","doi":"10.1186/s10020-026-01571-9","DOIUrl":"10.1186/s10020-026-01571-9","url":null,"abstract":"<p><strong>Background: </strong>Diabetic cardiomyopathy (DCM) is characterized by microvascular dysfunction. While vascular endothelial cells (ECs) have been widely studied, the role of cardiac lymphatic ECs (LECs) in DCM remains unknown.</p><p><strong>Methods: </strong>A mouse model of DCM was induced by a high-fat diet (HFD) with streptozotocin (STZ) injection. We performed single-cell RNA sequencing (scRNA-seq) on cardiac tissues from mice with DCM and control mice. We then applied clustering, RNA velocity, pseudotime analysis, and CellChat cell-cell communication analysis to define lymphatic endothelial cell (LEC) heterogeneity and underlying regulatory networks.</p><p><strong>Results: </strong>Our analysis revealed profound pathological remodeling of the cardiac lymphatic architecture in diabetic hearts, marked by decreased LEC numbers and impaired function. Cell-cell communication analysis demonstrated impaired VEGF-C/VEGFR3 signaling between venous ECs (VECs) and LECs in diabetic hearts. We identified the upregulation of pyruvate dehydrogenase kinase 4 (PDK4) expression in diabetic LECs as a key driver of metabolic reprogramming, leading to impaired cell migration.</p><p><strong>Conclusions: </strong>This study mapped the profile of LECs in diabetic hearts and revealed a dual pathogenic mechanism involving metabolic disorders driven by PDK4 and disruption of venous-lymphatic communication. These findings may provide new strategies for the treatment of DCM.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456454","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}