Frontiers in molecular medicine最新文献_第2页

Editorial: Targeted cancer therapy through metabolic pathways. 社论：通过代谢途径靶向治疗癌症。

Frontiers in molecular medicine Pub Date : 2026-05-05 eCollection Date: 2026-01-01 DOI: 10.3389/fmmed.2026.1842647

Prasanna Srinivasan Ramalingam, Md Sadique Hussain, Shreyas Ramchandra Gaikwad, Sivakumar Arumugam

引用次数: 0

Mapping the future of medicine through digital twins. 通过数字双胞胎绘制医学的未来。

Frontiers in molecular medicine Pub Date : 2026-04-29 eCollection Date: 2026-01-01 DOI: 10.3389/fmmed.2026.1840371

Frank Emmert-Streib, Shailesh Tripathi, Olli Yli-Harja

引用次数: 0

Sirtuin 1 is a key molecular link between cellular senescence and heart failure. Sirtuin 1是细胞衰老和心力衰竭之间的关键分子联系。

Frontiers in molecular medicine Pub Date : 2026-04-28 eCollection Date: 2026-01-01 DOI: 10.3389/fmmed.2026.1818104

Jan Krekora, Jarosław Drożdż, Janusz Blasiak

{"title":"Sirtuin 1 is a key molecular link between cellular senescence and heart failure.","authors":"Jan Krekora, Jarosław Drożdż, Janusz Blasiak","doi":"10.3389/fmmed.2026.1818104","DOIUrl":"10.3389/fmmed.2026.1818104","url":null,"abstract":"Cellular senescence, a state where cells permanently exit the cycle but remain metabolically active, plays a role in cardiovascular diseases (CVD), including heart failure (HF). Senescent cells accumulate in aging and stressed heart tissue, releasing pro-inflammatory cytokines, chemokines, and enzymes that affect endothelial cells. This ongoing inflammation exacerbates cardiac damage, induces endothelial dysfunction, and triggers secondary senescence across various cardiac cell types. Senescent cardiomyocytes contribute to reduced systolic function by causing mitochondrial damage, impaired contractility, and metabolic dysfunction, leading to lower cardiac output and symptoms such as fatigue and exercise intolerance in HF patients. Additionally, inflammation from senescent endothelial cells and loss of microvasculature impair coronary blood flow and oxygen delivery, worsening symptoms such as shortness of breath, angina-like discomfort, and fluid retention by disrupting cardiac energy metabolism and increasing filling pressures. A key factor linking cellular senescence with HF is sirtuin 1 (SIRT1), a histone deacetylase with antioxidant activity. SIRT1 acts as a hormetic regulator in the heart, being beneficial within a narrow range but potentially harmful when overstimulated. As drugs targeting senescence are emerging to treat CVD, it is important to evaluate how SIRT1 may influence the connection between senescence and HF to improve anti-senescent therapies. In this narrative/perspective review, we explore the molecular mechanisms underlying senescence in HF development and how SIRT1 might modulate these processes for therapeutic benefit.","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"6 ","pages":"1818104"},"PeriodicalIF":0.0,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13160494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147936145","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}

引用次数: 0

Molecular mechanisms underlying psoriasis and depression: an integrated analysis using mendelian randomization, transcriptomics, and single-cell sequencing. 银屑病和抑郁症的分子机制：使用孟德尔随机化、转录组学和单细胞测序的综合分析。

Frontiers in molecular medicine Pub Date : 2026-04-15 eCollection Date: 2026-01-01 DOI: 10.3389/fmmed.2026.1770665

Baojun De, Wenfeng Bao, Nagongbilige Hea, Jun Fang

{"title":"Molecular mechanisms underlying psoriasis and depression: an integrated analysis using mendelian randomization, transcriptomics, and single-cell sequencing.","authors":"Baojun De, Wenfeng Bao, Nagongbilige Hea, Jun Fang","doi":"10.3389/fmmed.2026.1770665","DOIUrl":"10.3389/fmmed.2026.1770665","url":null,"abstract":"Background: Psoriasis, an immune-mediated systemic inflammatory disease affecting skin, vessels, and joints, often co-occurs with depression. Routine depression screening is vital, as mood disorders link to inflammation, visible lesions, and functional limitations.Methods: The study integrated Mendelian randomization (MR), transcriptomics, and single-cell omics via public databases to explore comorbidity mechanisms.Results: MR identified 340 psoriasis-related and 307 depression-related eQTL-gene associations; 9 intersected. LASSO found 4 key Genes (MAP3K20, WARS2, TBXAS1, ABHD15), enriched in IL-17/NF-κB/FoxO pathways, cholesterol metabolism, and synaptic cycling. They correlated with immune infiltration, ferroptosis, and specific cell localization. Folic acid (from CTD) targeted 3 genes.Conclusion: These 4 genes mediate comorbidity via inflammation, immune metabolism, and ferroptosis. Folic acid pathways have therapeutic value, laying a foundation for precision therapy.","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"6 ","pages":"1770665"},"PeriodicalIF":0.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147790559","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}

引用次数: 0

HIF1α reinforces PPARγ-dependent metabolic rechanneling to support lipid accumulation in adipocytes. HIF1α增强ppar γ依赖的代谢再通道，支持脂肪细胞中的脂质积累。

Frontiers in molecular medicine Pub Date : 2026-02-23 eCollection Date: 2026-01-01 DOI: 10.3389/fmmed.2026.1716464

Chaonan Zhu, Meiqian Wu, Minh Duc Pham, Yue Wang, Arka Provo Das, Yijie Mao, Peter Mirtschink, Ting Yuan, Jaya Krishnan

{"title":"HIF1α reinforces PPARγ-dependent metabolic rechanneling to support lipid accumulation in adipocytes.","authors":"Chaonan Zhu, Meiqian Wu, Minh Duc Pham, Yue Wang, Arka Provo Das, Yijie Mao, Peter Mirtschink, Ting Yuan, Jaya Krishnan","doi":"10.3389/fmmed.2026.1716464","DOIUrl":"10.3389/fmmed.2026.1716464","url":null,"abstract":"Introduction: Adipose tissue hypoxia is a hallmark of obesity and partly contributes to metabolic dysfunction through effects on differentiated adipocytes. Although hypoxia-inducible factor 1α (HIF1α) is a key transcriptional mediator of hypoxic responses, its state-dependent metabolic role remains incompletely defined in mature adipocytes. Herein, we investigate how HIF1α regulates lipid metabolism in differentiated adipocytes under nutrient excess conditions.Methods: An adipocyte-specific Hif1α knockout mouse model was subjected to high-fat diet feeding in vivo. Adipose mass, adipocyte size, glucose tolerance, and insulin sensitivity were assessed. Metabolic and enzymatic analyses focused on lipid anabolic pathways, including glycolysis-linked glycerolipid biosynthesis and PPARγ-dependent programs.Results: Adipocyte-specific deletion of Hif1α attenuated adipocyte hypertrophy, resulting in reduced adipose mass as well as improved systemic glucose tolerance and insulin sensitivity during high-fat diet feeding. Mechanistically, HIF1α reinforced PPARγ-dependent lipid anabolic programs by coordinating glycolytic flux with glycerolipid biosynthesis to promote the rechanneling of glucose-derived intermediates into triacylglyceride synthesis.Discussion: Together, these findings provide metabolic and enzymatic validations of a late-stage, state-dependent HIF1α-PPARγ lipid storage program and implicate the glycerol-3-phosphate dehydrogenase 1 (GPD1)-glycerol-3-phosphate acyltransferase (GPAT) axis as a key molecular executor of hypertrophic lipid accumulation in differentiated adipocytes.","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"6 ","pages":"1716464"},"PeriodicalIF":0.0,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12968251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147438134","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}

引用次数: 0

CD19 exon 2 skipping is a potential prognostic correlate of anti-CD19 CAR-T therapy relapse. CD19外显子2跳变是抗CD19 CAR-T治疗复发的潜在预后相关因素。

Frontiers in molecular medicine Pub Date : 2026-02-12 eCollection Date: 2026-01-01 DOI: 10.3389/fmmed.2026.1763390

Søren Helweg Dam, Giorgia Moranzoni, Magnus Haraldson Høie, Signe Modvig, Karin A W Wadt, Bodil Als-Nielsen, Kjeld Schmiegelow, Kristoffer Vitting-Seerup, Mike Bogetofte Barnkob, Lars Rønn Olsen

{"title":"CD19 exon 2 skipping is a potential prognostic correlate of anti-CD19 CAR-T therapy relapse.","authors":"Søren Helweg Dam, Giorgia Moranzoni, Magnus Haraldson Høie, Signe Modvig, Karin A W Wadt, Bodil Als-Nielsen, Kjeld Schmiegelow, Kristoffer Vitting-Seerup, Mike Bogetofte Barnkob, Lars Rønn Olsen","doi":"10.3389/fmmed.2026.1763390","DOIUrl":"10.3389/fmmed.2026.1763390","url":null,"abstract":"Relapse following anti-CD19 chimeric antigen receptor (CAR) T cell therapy remains a concern in the treatment of refractory B-cell malignancies. Although the CD19Δexon2 splice variant has been linked to treatment failure, reliable pre-treatment biomarkers for relapse risk are lacking. Here, we analyzed RNA-sequencing data from a small publicly available cohort of four anti-CD19 CAR-T-treated B-cell acute lymphoblastic leukemia patients, including one responder, one non-responder, and two who relapsed after initial response. We quantified the percent spliced in (PSI) of CD19 exon 2, as a proxy for CD19Δexon2 abundance before and after treatment. The patient with the lowest pre-treatment exon 2 PSI (i.e., highest estimated abundance of CD19Δexon2) experienced the earliest relapse, whereas the complete responder showed no detectable exon 2 skipping. In silico protein structure modeling indicated reduced structural stability of the FMC63 epitope region in the CD19Δexon2 variant, supporting a potential mechanistic link between exon 2 exclusion and antigen escape. Analysis of larger RNA-sequencing datasets from CAR-T treatment-naïve B-cell malignancies and healthy tissues revealed low-level exon 2 skipping in some individuals across both malignant and normal B cells. These findings suggest that CD19 exon 2 skipping may correlate with relapse after CAR-T therapy, and its presence in treatment-naïve individuals highlights its potential for evaluation as an RNA- or qPCR-based biomarker in future studies.","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"6 ","pages":"1763390"},"PeriodicalIF":0.0,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12935319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147313220","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}

引用次数: 0

Association of specific HLA alleles in patients with interstitial cystitis suggesting autoimmunity. 间质性膀胱炎患者特异性HLA等位基因相关性提示自身免疫。

Frontiers in molecular medicine Pub Date : 2025-12-04 eCollection Date: 2025-01-01 DOI: 10.3389/fmmed.2025.1712660

Inna Tabansky Stern, Jiayao Wang, Robert M Moldwin, Jason M Kim, Jason H Singh, Derek C Tran, Souhel Najjar, Melis Akinci, Alexis Howard, Joseph E Duke-Cohan, Marwa Belhaj, Jonathan Stevens, William J Lane, Lori A Birder, Edwin K Jackson, Derin B Keskin, Guanglan Zhang, Joel N H Stern

{"title":"Association of specific HLA alleles in patients with interstitial cystitis suggesting autoimmunity.","authors":"Inna Tabansky Stern, Jiayao Wang, Robert M Moldwin, Jason M Kim, Jason H Singh, Derek C Tran, Souhel Najjar, Melis Akinci, Alexis Howard, Joseph E Duke-Cohan, Marwa Belhaj, Jonathan Stevens, William J Lane, Lori A Birder, Edwin K Jackson, Derin B Keskin, Guanglan Zhang, Joel N H Stern","doi":"10.3389/fmmed.2025.1712660","DOIUrl":"10.3389/fmmed.2025.1712660","url":null,"abstract":"Interstitial cystitis/bladder pain syndrome (IC/BPS) with Hunner Lesions (Hunner Type Interstitial Cystitis or HIC) is characterized by lesions on the bladder wall. Previous work on these lesions identified B cells and monocytes within the lesion. However, the overall role of the adaptive immune system in the disorder remains uncertain. In this study, we performed HLA sequencing on 12 IC/BPS patients with HIC and 7 Non Hunner Type IC (NHIC) patients, and identified HLA-DQB1*02:02 and HLA-DRB1*07:01:01 have a significant association with HIC. This pilot study provides genetic evidence supporting a potential autoimmune component in HIC and may help define the pathogenesis of at least one subtype of IC/BPS, and lay the groundwork for identifying the etiology of IC/BPS as a disease complex. Identifying the mechanisms can also open new approaches to treatment. Identifying an HLA haplotype associated with HIC would indicate that it is autoimmune.","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"5 ","pages":"1712660"},"PeriodicalIF":0.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12712699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145806514","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}

引用次数: 0

Advancing AAV vector manufacturing: challenges, innovations, and future directions for gene therapy. 推进AAV载体制造：基因治疗的挑战、创新和未来方向。

Frontiers in molecular medicine Pub Date : 2025-12-03 eCollection Date: 2025-01-01 DOI: 10.3389/fmmed.2025.1709095

N Charan S S Kowshik, Pushpendra Singh

{"title":"Advancing AAV vector manufacturing: challenges, innovations, and future directions for gene therapy.","authors":"N Charan S S Kowshik, Pushpendra Singh","doi":"10.3389/fmmed.2025.1709095","DOIUrl":"10.3389/fmmed.2025.1709095","url":null,"abstract":"Adeno-Associated Virus (AAV) vectors are at the forefront of gene therapy, offering transformative therapeutic potential for many genetic disorders. However, the translation of this promise into accessible treatments is constrained by manufacturing challenges, including process variability, low yields, and scalability challenges. This review provides a comprehensive framework for establishing robust AAV-based gene therapy manufacturing processes by evaluating industry challenges and recent technological innovations. We studied the end-to-end AAV-based gene therapy manufacturing process, from upstream unit operations such as cell culture and transfection to downstream purification and fill-finish operations. Key upstream innovations highlighted include high-density perfusion cultures, advanced single- and dual-plasmid systems, and next-generation transfection reagents that collectively enhance the overall process quality and viral vector productivity. In the realm of downstream processing, recent advancements in serotype-agnostic affinity chromatography and ion-exchange chromatographic purifications have enhanced the critical separation of full capsids from empty capsids. The implementation of a quality-by-design framework is the heart of the AAV-based gene therapy manufacturing process. We emphasize the necessity of a rigorous process characterization, utilizing validated scale-down models and design of experiments, as a prerequisite for establishing a robust control strategy with defined proven and normal operating ranges. This data-driven approach not only mitigates process inconsistency, but it also serves as the foundation for an effective process validation and regulatory compliance. Looking ahead, the integration of artificial intelligence and continuous manufacturing methodologies will be pivotal in expediting the development of safer, more efficacious, and personalized AAV-based gene therapies.","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"5 ","pages":"1709095"},"PeriodicalIF":0.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12709507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783675","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}

引用次数: 0

MYC is in the CARDs: CBM complexes coordinate immune and MYC-dependent cellular function. MYC在卡片中：CBM复合物协调免疫和MYC依赖性细胞功能。

Frontiers in molecular medicine Pub Date : 2025-11-19 eCollection Date: 2025-01-01 DOI: 10.3389/fmmed.2025.1731823

Stanley B DeVore, Gurjit K Khurana Hershey

引用次数: 0

Antibody-drug conjugates targeting the cadherin, claudin and nectin families of adhesion molecules. 靶向黏附分子中的钙粘蛋白、粘连蛋白和连接蛋白家族的抗体-药物偶联物。

Frontiers in molecular medicine Pub Date : 2025-10-14 eCollection Date: 2025-01-01 DOI: 10.3389/fmmed.2025.1661016

Masuko Katoh, Yohann Loriot, Izuma Nakayama, Akinobu Hamada, Kohei Shitara, Masaru Katoh

{"title":"Antibody-drug conjugates targeting the cadherin, claudin and nectin families of adhesion molecules.","authors":"Masuko Katoh, Yohann Loriot, Izuma Nakayama, Akinobu Hamada, Kohei Shitara, Masaru Katoh","doi":"10.3389/fmmed.2025.1661016","DOIUrl":"10.3389/fmmed.2025.1661016","url":null,"abstract":"The classical cadherin (CDH), claudin (CLDN) and nectin families of transmembrane-type adhesion molecules are located at adherens or tight junctions in epithelial cells but diffuse to the nonjunctional cell surface in solid tumors with epithelial-mesenchymal plasticity. Human/humanized antibody-drug conjugates (ADCs) with chemical linkers and cytotoxic payloads have been developed for the treatment of malignancies. Here, the clinical development of ADCs that target CDH6, CDH17, CLDN6, CLDN18.2 and NECTIN4 is reviewed. Enfortumab vedotin is an NECTIN4-targeting antibody-drug conjugate that is approved for the treatment of urothelial cancer, whereas other ADCs or derivatives that target NECTIN4, such as bulumtatug fuvedotin, SHR-A2102 and zelenectide pevedotin, are being studied in randomized phase III clinical trials. In contrast, arcotatug tavatecan, garetatug rezetecan, sonesitatug vedotin and tecotabart vedotin are anti-CLDN18.2 ADCs in phase III clinical trials for the treatment of CLDN18.2-positive gastric or gastroesophageal junction adenocarcinomas, and raludotatug deruxtecan is an anti-CDH6 ADC in a phase II/III clinical trial for the treatment of platinum-resistant ovarian cancer. ADCs that target cell-cell adhesion molecules are a rapidly emerging class of cancer therapeutics, and bispecific ADCs and longitudinal companion diagnostics are emerging to further improve the clinical benefits of conventional ADCs.","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"5 ","pages":"1661016"},"PeriodicalIF":0.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12558957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145402879","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}

引用次数: 0