Journal of molecular medicine (Berlin, Germany)最新文献

{"title":"Kv1.3 regulates macrophage immune function through PI3K/AKT signaling pathway to alleviate metabolic dysfunction-associated steatohepatitis.","authors":"Ting Ke, Wen-Jun Zhen, Xi-Xi Chen, Hao Wang, Shi Chen, Yuan-Yuan Tian, Ye-Tao Wang, Lei Zhang, Bao-Ming Wu","doi":"10.1007/s00109-026-02666-w","DOIUrl":"10.1007/s00109-026-02666-w","url":null,"abstract":"<p><strong>Background and aim: </strong>The progression of metabolic dysfunction-associated steatohepatitis (MASH) is closely linked to macrophage-mediated inflammatory responses. The role of Kv1.3, a key voltage-gated potassium channel regulating macrophage function, in MASH remains unclear. This study investigated Kv1.3 blockade's therapeutic potential in MASH and its mechanism, focusing on the PI3K/AKT signaling pathway.</p><p><strong>Methods: </strong>A Western diet (WD)-induced mouse model of MASH was established, and hepatic Kv1.3 was knocked down via AAV8-Kv1.3-shRNA. Hepatic steatosis, inflammation, and macrophage infiltration were evaluated. In vitro, LPS-stimulated RAW264.7 macrophages were treated with the Kv1.3 inhibitor ShK-186 to assess inflammatory cytokine (IL-6, TNF-α) production and migration. The GEO dataset (GSE222922) validated the PI3K/AKT signaling pathway involvement.</p><p><strong>Results: </strong>Kv1.3 expression was significantly increased in WD-induced MASH mouse livers. Hepatic Kv1.3 knockdown alleviated liver injury, steatosis, and inflammation. In vitro, ShK-186 inhibited LPS-induced macrophage migration and cytokine production, and significantly reduced the PI3K/AKT phosphorylation. These effects were reversed by the PI3K agonist 740Y-P, confirming that Kv1.3 regulates macrophage function via the PI3K/AKT signaling.</p><p><strong>Conclusion: </strong>Kv1.3 modulates macrophage inflammation and migration through the PI3K/AKT signaling pathway, promoting MASH progression. Kv1.3 knockdown ameliorates MASH pathology, highlighting it as a promising therapeutic target.</p><p><strong>Key messages: </strong>Kv1.3 drives MASH via macrophage PI3K/AKT signaling, worsening liver inflammation Macrophage Kv1.3 knockdown alleviates MASH pathology in WD-fed mice Kv1.3 is a potential therapeutic target for MASH, modulating liver inflammation.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147663624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic value of circulating glypican-4 in chronic heart failure.","authors":"Nora Schwegel, Viktoria Höller, Viktoria Santner, David Kajetan Zach, Jakob Lugitsch, Axel Muendlein, Eva Maria Brandtner, Andreas Leiherer, Heinz Drexel, Arthur Mader, Andrea Borenich, Stefan Pilz, Martin Grübler, Markus Wallner, Klemens Ablasser, Ewald Kolesnik, Andreas Zirlik, Dirk von Lewinski, Nicolas Verheyen","doi":"10.1007/s00109-026-02667-9","DOIUrl":"10.1007/s00109-026-02667-9","url":null,"abstract":"<p><p>Glypican-4 (GPC-4), an endothelial cell surface protein, is released into the circulation in the context of ischemia, inflammation, neurohumoral activity, and shear stress. This study aimed to investigate the prognostic value of GPC-4 in chronic heart failure. GPC-4 concentrations were determined in two prospective cohorts: patients with chronic heart failure with reduced ejection fraction (HFrEF), and with transthyretin amyloid cardiomyopathy (ATTR-CM). Multivariable Cox regression analyses were adjusted for age, sex, estimated glomerular filtration rate, N-terminal B-type natriuretic peptide, and left ventricular ejection fraction. In HFrEF (n = 205, median age 66 years, 22% women), 58 patients (28%) died, 18 (9%) from cardiovascular cause, and 46 patients (22%) were hospitalized for worsening heart failure (WHF) during 4.2 years follow-up. In ATTR-CM (n = 121, median age 76 years, 12% women), 34 patients (28%) died, 12 (10%) from cardiovascular cause, and 32 patients (26%) had a WHF hospitalization during 2.2 years follow-up. Baseline GPC-4 (median [interquartile range]) levels were 1553 (1041, 1950) pg/ml in HFrEF, and 2071 (1579, 2893) pg/mL in ATTR-CM. In HFrEF, GPC-4 was independently associated with all-cause mortality (HR 1.69, 95%CI 1.22-2.32, p = 0.003) and cardiovascular mortality (HR 1.61, 95%CI 1.01-2.56, p = 0.045), but not with WHF hospitalizations. Conclusively, in ATTR-CM, GPC-4 independently predicted all-cause mortality (HR 1.96, 95%CI 1.12-3.44, p = 0.018), but not cardiovascular mortality and WHF hospitalizations. GPC-4 carries strong prognostic value for all-cause death in chronic heart failure across various etiologies, but not for heart-failure specific outcomes. Further studies are warranted to elucidate its value in cardiovascular disease. KEY MESSAGES : Glypican-4 rises with ischemia, inflammation, neurohumoral activity, and shear stress. Circulating glypican-4 predicts prognosis in chronic heart failure, regardless of cause. Glypican-4 predicted all-cause death in heart failure with reduced ejection fraction and restrictive cardiomyopathy, but not heart failure-specific outcomes.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13056786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147629796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of acute blue light irradiation on the molecular clock and markers associated with photoaging in skin cell models.","authors":"Agnia Vibriani, Xinyue Chen, Susumu Kajiwara, Kanami Orihara","doi":"10.1007/s00109-026-02664-y","DOIUrl":"10.1007/s00109-026-02664-y","url":null,"abstract":"<p><p>The increased reliance on digital devices in our daily lives has exposed humans to intense levels of high-energy blue light. However, the harmful effects of blue light irradiation on human skin are less understood than UV irradiation. Notably, we demonstrated that blue light induces skin photoaging through a novel mechanism involving disruption of the circadian rhythm. An in vitro study using human keratinocyte cells and dermal fibroblasts was conducted. The results showed that blue light irradiation triggers cellular senescence and downregulates key aging-associated markers, including extracellular matrix components, epithelial barrier protein, NAD⁺-dependent metabolic stress sensor (SIRT1), and aging-sensitive NAD + producer (NAMPT). Remarkably, we found that blue light irradiation disrupted the circadian rhythm at the cellular level. This is evidenced by phase-shifted PER3 mRNA levels, loss of BMAL1 protein rhythmicity, and altered temporal expression of aging-associated markers. Our results demonstrate that blue light triggers skin photoaging through circadian disruption, establishing a novel mechanistic pathway that transforms our understanding of photoaging complexity. This study initiates the framework for developing chronotherapy-based interventions to address the growing epidemic of digital device-associated skin damage and, therefore, could be used as a scientific foundation for developing novel active compounds in cosmeceutical products. KEY MESSAGES: We identified novel mechanisms in blue light-induced skin photoaging. Acute blue light exposure induced cellular senescence in skin cells. Acute blue light exposure downregulated key aging-associated markers in skin cells. Acute blue light exposure disrupted the circadian rhythm of skin cells. Targeting circadian rhythm offers a promising therapeutic route for skin photoaging.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13056783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147629802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative multimodal transcriptomics identifies a cancer-associated fibroblast membrane signature for predicting prognosis and therapeutic response in pancreatic ductal adenocarcinoma.","authors":"Leshi Zhuang, Wei Zhang, Jun Wu, Jian Cao, Liang Feng, Shubo Cao","doi":"10.1007/s00109-026-02669-7","DOIUrl":"10.1007/s00109-026-02669-7","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) are central to the pancreatic ductal adenocarcinoma (PDAC) microenvironment, promoting tumor progression and therapeutic resistance. However, the expression landscape of CAF membrane proteins in PDAC remains poorly defined. We integrated scRNA-seq (n = 33; 87,949 cells), spatial transcriptomics (n = 2; 7,011 spots), and bulk RNA-seq (n = 7; 642 samples) to systematically identify PDAC-specific CAF membrane genes. A LASSO-based Cox model was developed to construct a prognostic signature, PaFMS, and evaluated through multi-cohort validation. Functional enrichment, immune infiltration, drug sensitivity, and immunotherapy response analyses were further conducted. Validation was performed using multiple database-driven analyses. We identified a PDAC-enriched myoCAF-c1 cluster closely associated with epithelial-mesenchymal transition (EMT) and angiogenesis. From this cluster, 33 candidate CAF membrane genes were defined, whose protein-protein interactions were predominantly linked to extracellular matrix organization and collagen remodeling, and spatially colocalized with myoCAF-c1 and EMT regions. An 11-gene prognostic signature, PaFMS that robustly stratified patients across six independent cohorts, achieving high predictive accuracy for overall survival. High-risk patients exhibited proliferative signaling activation, immune suppression, and reduced T/B-cell infiltration. PaFMS was associated with responses to 33 anticancer agents and predicted enhanced benefit from anti-PD-L1 immunotherapy in the low-risk group. Multi-cohort validation confirmed the expression specificity of PaFMS genes, including PLAU, TMEM158, and TRIM59. Together, these findings reveal that myoCAF-c1 promotes angiogenesis and tumor progression, and establish PaFMS as a robust CAF membrane-based prognostic model in PDAC with potential utility for precision prognosis and therapeutic decision-making. KEY MESSAGES: Integrated single-cell, spatial, and bulk RNA-seq analyses identified PDAC-specific CAF membrane genes. Discovered a PDAC-enriched myoCAF-c1 subtype linked to EMT and angiogenesis. Developed an 11-gene CAF membrane-based prognostic model (PaFMS) validated across six cohorts. PaFMS predicts patient survival, drug sensitivity, and immunotherapy response in PDAC.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13053443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147629803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil-related gene expression profile is associated with future paediatric bronchiectasis exacerbations.","authors":"Hannah E O'Farrell, Vikas Goyal, Anne B Chang, Keith Grimwood, Michael Cheng, Stephanie T Yerkovich, Katherine J Baines","doi":"10.1007/s00109-026-02662-0","DOIUrl":"10.1007/s00109-026-02662-0","url":null,"abstract":"<p><p>Acute respiratory exacerbations in bronchiectasis are important as they impair quality of life and are associated with accelerated lung function decline. Yet, no validated methods exist to identify children at increased risk of exacerbations. We therefore determined if peripheral blood gene expression (GE) signatures can identify those at risk of an impending exacerbation. Thirty-one children with bronchiectasis had RNA extracted from peripheral blood collected whilst they were clinically stable, with 22 having an exacerbation during the next 3 months. Microarray assays using the HumanHT-12 v4.0 Expression BeadChip identified differentially expressed genes (p value ≤ 0.05, fold change > 1.5). The top targets were verified using real-time quantitative polymerase chain reaction (rt-qPCR) assays, and receiver operating characteristics and area under the curve (AUC) were assessed. Functional analysis of these genes was performed using Ingenuity Pathway Analysis. Overall, 647 entities were significantly dysregulated (p < 0.05) in the exacerbation group (n = 22), and pathway analysis identified neutrophil degranulation as the dominant affected pathway, which was also significantly inhibited (p < 0.001). Forty entities (32 genes) were associated with a future exacerbation (p ≤ 0.05, fold change ≥ 1.5) and six genes (ANXA3, ALAS2, DEFA1, ALPL, SNCA, PROK2) were verified using RT-qPCR (all p < 0.04) as the most discriminatory. DEFA1 and ANXA3 had the highest AUC (0.92, 95% confidence interval [CI] 0.82-1.00, and 0.87, 95% CI 0.73-1.00, respectively). We identified neutrophil-associated genes from peripheral blood that could be potential biomarkers for children with bronchiectasis at increased risk of exacerbations during the next 3 months. These GE signatures warrant further investigation and validation in larger, independent cohorts. KEY MESSAGES: Exacerbations in paediatric bronchiectasis are important. Peripheral blood gene expression may help identify children at risk of exacerbations. Six neutrophil-associated genes were associated with a future exacerbation. Identifying predictive gene expression signatures warrants further investigation.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13038636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147597558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic spontaneous urticaria treatments and purinergic signaling: a therapeutic possibility.","authors":"Michelli Fontana, Júlia Leão Batista Simões, Geórgia de Carvalho Braga, Mauricio Fontana, João Carlos Menta Filho, Margarete Dulce Bagatini","doi":"10.1007/s00109-026-02670-0","DOIUrl":"10.1007/s00109-026-02670-0","url":null,"abstract":"<p><p>Urticaria is a skin lesion characterized by a central swelling area of varying sizes, usually surrounded by erythema and accompanied by itching or a burning sensation. Recurrence for at least six weeks characterizes chronic urticaria, a condition that has no cure, only treatment to minimize symptoms. The available pharmacological therapies show variable success and do not regulate the inflammatory balance of the skin in the long term. Therefore, it is essential to evaluate treatment possibilities to seek new symptom management approaches. In this regard, this study addresses the currently available therapies, linking the disease's pathophysiology with purinergic signaling to identify new therapeutic possibilities. In this respect, extracellular ATP is related to mast cells degranulation in the skin, which affects urticaria. Considering other dermatological diseases that present an inflammatory response, the purinergic receptor P2X7 is related to inflammation in several pathological skin conditions, such as psoriasis, dermatitis and pruritus. P2X7 engagement also contributes to ATP-mediated mast cell degranulation. Therefore, evaluating the expression of purinergic receptors in the skin of patients with chronic spontaneous urticaria, along with ATP levels in urticarial lesions, may help elucidate the therapeutic potential of targeting this purinergic pathway. KEY MESSAGES: Many patients are refractory to licensed therapies of H1antihistamines and omalizumab. Cyclosporine and other immunosuppressants are studied for refractory patients. Probiotics as adjuncts to antihistamines are studied to reduce symptoms. P2X7 receptor links to inflammatory skin diseases and may offer new therapy approach.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13038462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147597602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TGF-β-induced autophagy in pulmonary artery endothelial cells associated with chronic thromboembolic pulmonary hypertension.","authors":"Ying-Ju Lai, Yen-Lin Huang, Ching-Yen Tsai, Po-Ru Chen, Chi-Jen Chang, Yung-Hsin Yeh, Celina De Almeida, Hsao-Hsun Hsu","doi":"10.1007/s00109-026-02661-1","DOIUrl":"10.1007/s00109-026-02661-1","url":null,"abstract":"<p><p>Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive vascular disorder characterized by persistent thromboembolic obstruction and fibrotic remodeling of the pulmonary arteries. Although autophagy has been implicated in various forms of pulmonary hypertension, its specific role in CTEPH pathogenesis remains unclear. In this study, histological, immunohistochemical, and molecular analyses of pulmonary artery lesions from CTEPH patients revealed increased collagen deposition and elevated expression of autophagy markers beclin-1 and microtubule-associated protein 1A/1B-light chain 3 (LC3) compared to non-CTEPH controls. Primary pulmonary artery endothelial cells (PAECs) derived from CTEPH patients exhibited dysregulated autophagy-related protein expression. Mechanistically, TGF-β stimulation induced autophagy via the Smad3 signaling pathway. Notably, riociguat, a soluble guanylate cyclase stimulator approved for CTEPH, modulated autophagy-related proteins in vitro. In hypoxia- and TGF-β-induced pulmonary hypertension mouse models, riociguat attenuated LC3 but not beclin-1 expression and significantly reduced right ventricular systolic pressure. These findings suggest that LC3 may be a key autophagy marker in CTEPH. These findings identify the TGF-β/Smad3-LC3 axis as a critical mechanism driving CTEPH and suggest that pharmacological modulation of autophagy, particularly via riociguat, offers a promising therapeutic opportunity, especially for patients ineligible for surgical intervention. KEY MESSAGES: Beclin-1 and LC3, key autophagy markers, are upregulated in thrombofibrotic pulmonary arteries from patients with CTEPH. TGF-β activates autophagy in pulmonary artery endothelial cells through the Smad3 signaling pathway. Riociguat treatment downregulates LC3 expression, improves pulmonary hemodynamics, and reduces vascular remodeling in experimental PH models. LC3 as a potential biomarker and therapeutic target in the progression of CTEPH driven by autophagy.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147583459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring a plasma proteomic biosignature associated with cardiac involvement in Fabry disease.","authors":"Thi Hai Yen Nguyen, Quang Thu Nguyen, Franklin Ducatez, Abdellah Tebani, Phuoc Long Nguyen, Soumeya Bekri","doi":"10.1007/s00109-026-02663-z","DOIUrl":"10.1007/s00109-026-02663-z","url":null,"abstract":"<p><p>Fabry disease (FD) is an X-linked lysosomal disorder caused by a deficiency in α-galactosidase A, leading to the accumulation of globotriaosylceramide (Gb3) and lysoGb3. While this accumulation was long seen as the leading cause of symptoms, FD pathogenesis now involves complex mechanisms like autophagy dysregulation, inflammation, oxidative stress, and inter-organelle communication. Cardiovascular diseases (CVD) remain a significant reason for premature death in FD. Gaining a better understanding of cardiac pathophysiology and developing new biomarkers for early detection and monitoring in FD are still essential. In this study, we proposed an FD-CVD protein signature by analyzing the plasma proteome of 55 FD patients, including 18 with CVD and 37 without (woCVD), and 30 non-FD controls. We found 141 altered proteins in FD-CVD compared to FD-woCVD. Among them, 38 differential proteins are related to cardiometabolism. Moreover, ten proteins were identified as potential biomarkers for differentiating FD-CVD from FD-woCVD. The 10-protein signature performed well in RF and partial least squares discriminant analysis models but had limited predictive ability in support vector machine and logistic regression. Importantly, this biosignature demonstrated an ability to classify FD and non-FD controls, regardless of CVD complications, with AUCs greater than 0.90. Using a local interpretable model-agnostic explanation, the RF model interpretation revealed the classification rule for FD-woCVD and highlighted the significance of GDF15, NOS1, CCN5, CTSF, and NAAA. Our findings suggest an early indication of combined cardiac involvement in FD, paving the way for future validation studies that may ultimately inform personalized treatment before irreversible heart damage develops. KEY MESSAGES: Cardiovascular diseases (CVD) remain the leading cause of premature death in Fabry. A ten-protein signature was identified to differentiate Fabry with and without CVD. The protein signature could classify Fabry with controls regardless of CVD status.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147577439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of miR-146a induces cardiomyocyte proliferation after myocardial infarction through targeting Kctd15.","authors":"Chenrui Zhang, Xuejiao Wei, Yongqin He, Xingwei Hu, Mengsha Li, Bing Li","doi":"10.1007/s00109-026-02658-w","DOIUrl":"10.1007/s00109-026-02658-w","url":null,"abstract":"<p><p>Accumulating evidence strongly confirms that microRNAs (miRNAs) play a pivotal role in the development and progression of cardiovascular diseases. Specifically, miR-146a has been demonstrated to be implicated in the pathogenesis of multiple cardiac diseases. Nevertheless, the role of miR-146a in ischemic heart disease and its underlying molecular mechanism remains unclear. The expression levels of miR-146a during different stages of cardiac development were detected by quantitative polymerase chain reaction (qPCR). Gain-of-function and loss-of-function assays were conducted to evaluate the impact of miR-146a on cardiomyocyte (CM) proliferation. A myocardial infarction (MI) model was established, and M-mode echocardiography and Masson's trichrome staining were used to further investigate the effects of miR-146a on cardiac function recovery post-MI. Then, bioinformatics approaches, including RNA-seq, were utilized to predict Kctd15 as a potential target gene of miR-146a. Finally, a dual luciferase reporter assay and rescue experiment were used to verify miR-146a interactions with Kctd15. First, we found that miR-146a expression decreased with age. Then, overexpression of miR-146a inhibited CM proliferation, while miR-146a inhibition promoted CM proliferation in vitro. Similarly, overexpression of miR-146a was impaired in cardiac function recovery post-MI, whereas miR-146a deficiency improved post-MI cardiac function. Further, bioinformatics analysis suggested that miR-146a might regulate CM proliferation by targeting Kctd15, which was confirmed by overexpression of Kctd15 blocking the effect of miR-146a on CM proliferation. The current study demonstrates that miR-146a regulates CM proliferation through the miR-146a/Kctd15 mRNA/Kctd15 protein pathway, which may provide a potential molecular target for preventing and treating myocardial injury. KEY MESSAGES: Acute myocardial infarction (AMI) accounts for about 7 million deaths per year worldwide; the existing treatment methods such as thrombolysis and percutaneous coronary interventions cannot achieve a good prognosis. This study demonstrates that miR-146a is a negative regulator of CM proliferation and exerts its function through Kctd15. Kctd15 was first proposed to be related to CM proliferation. The study provides new support for endogenous CM proliferation and treatment in other cardiovascular diseases.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147577398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise and CD8⁺ T cells: mechanisms of immune modulation in antitumor responses.","authors":"Li Liu, Zhihao Deng, Ruiying Fang, Mi Zou, Junlin Ren, Yuan Gao, Jie Peng, Liang Hao","doi":"10.1007/s00109-026-02659-9","DOIUrl":"10.1007/s00109-026-02659-9","url":null,"abstract":"<p><p>CD8⁺ T cells are the core effector cells of antitumor immunity. However, their functionality is vulnerable to metabolic stress within the tumor microenvironment (TME), and they experience significant inhibition from immunosuppressive signals, such as PD-1/PD-L1 and myeloid-derived suppressor cells (MDSC). This review explores how exercise enhances CD8⁺ T-cell antitumor efficacy through multidimensional synergistic mechanisms. At the molecular level, exercise stimulates the IL-15/IL-15Rα signaling pathway and triggers the release of myokines such as IL-6 and IL-7. These changes considerably boost CD8⁺ T-cell proliferation, viability, and granzyme B-dependent tumoricidal activity. Concurrently, exercise improves metabolic adaptation and sustains antitumor effects via metabolic reprogramming, which involves enhancing mitochondrial oxidative phosphorylation and increasing lactate-mediated stemness. Moreover, exercise optimizes TME vascular structure, downregulates PD-L1 expression, reduces MDSC proportion, and transforms the immunosuppressive environment, thus facilitating CD8⁺ T-cell infiltration and long-term function. Preclinical studies have verified that exercise works in tandem with immune checkpoint inhibitors, like anti-PD-1, to improve T-cell homing and counteract the depletion phenotype through the CXCR3-CXCL9/10 axis. Despite the positive progress, the mechanisms of exercise intensity, individual heterogeneity, and dynamic regulation of TME need to be explored in depth. Future studies need to combine multi-omics and dynamic immune monitoring to develop personalized exercise interventions based on CD8⁺ T-cell profiles. Exercise provides a low-cost, low-risk adjuvant strategy for cancer immunotherapy by targeting CD8⁺ T-cell function and TME remodeling, and its clinical translational potential needs large-scale validation.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147494976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}