Cells

14 pages, 5870 KB

Open AccessArticle

Sexual Dimorphism of ZEB1 Expression and Function in Glioblastoma

by Ben E. Whittaker, Samuel Davies, Jeffrey C. F. Kwan, Annabelle Gordon-Smith and Florian A. Siebzehnrubl

Cells 2026, 15(15), 1428; https://doi.org/10.3390/cells15151428 - 6 Aug 2026

Viewed by 500

Abstract

Glioblastoma (GBM) exhibits marked sex differences in incidence, outcome, and molecular regulation, yet the mechanisms underlying these disparities remain poorly defined. ZEB1 is a neurodevelopmental transcription factor implicated in GBM progression and cellular plasticity, but its prognostic and functional relevance may differ by [...] Read more.

Glioblastoma (GBM) exhibits marked sex differences in incidence, outcome, and molecular regulation, yet the mechanisms underlying these disparities remain poorly defined. ZEB1 is a neurodevelopmental transcription factor implicated in GBM progression and cellular plasticity, but its prognostic and functional relevance may differ by sex. Here, we analyzed TCGA-GBM transcriptomic and clinical data to assess the relationship between ZEB1 expression, patient sex, and survival and to identify sex-specific transcriptional programs associated with ZEB1. Patients were stratified by ZEB1 expression and sex, followed by differential expression analysis, functional enrichment, and survival modeling. High ZEB1 expression was associated with improved overall survival in female patients but not in male patients. Sex-stratified transcriptomic analysis revealed distinct ZEB1-associated gene expression signatures, with enrichment of chromatin-modifying and demethylase-related pathways among male–female comparisons. Candidate Y-linked epigenetic regulators, including KDM5D and UTY, were differentially expressed in ZEB1-high male tumors. qPCR validation in male and female patient-derived GBM cell lines supported sex-dependent regulation of these candidates and showed that KDM5D and UTY expression was reduced following ZEB1 knockdown in male cells. Together, these findings identify a sex-dependent prognostic role for ZEB1 in GBM and suggest that ZEB1 interacts with sex-chromosome-linked epigenetic regulators to shape tumor transcriptional states. Full article

(This article belongs to the Special Issue Cellular Origin of Glioma: From Triggers to Treatments)

► Show Figures

Figure 1

20 pages, 50642 KB

Open AccessArticle

Genome-Wide Identification of the GDSL Gene Family and Functional Validation of DfDACX1 in Secondary Wall Synthesis in Dendrocalamus farinosus

by Xin Zhao, Yanwen Zhao, Mengqiu Chen, Man Tang, Zhijian Long, Gang Xu, Ying Cao and Shanglian Hu

Cells 2026, 15(15), 1427; https://doi.org/10.3390/cells15151427 - 6 Aug 2026

Viewed by 323

Abstract

GDSL esterases/lipases constitute a large and functionally versatile gene family in plants, yet their systematic characterization in bamboo—perennial woody grasses with exceptionally rapid shoot elongation—remains scarce. Here, we performed a genome-wide identification of the GDSL family in allohexaploid Dendrocalamus farinosus and characterized the [...] Read more.

GDSL esterases/lipases constitute a large and functionally versatile gene family in plants, yet their systematic characterization in bamboo—perennial woody grasses with exceptionally rapid shoot elongation—remains scarce. Here, we performed a genome-wide identification of the GDSL family in allohexaploid Dendrocalamus farinosus and characterized the function of a candidate gene in secondary wall synthesis. A total of 265 DfGDSL genes were identified and classified into nine clades; rice xylan deacetylases BS1 and DARX1 fell within Clade VIII, which harbors 75 members. Chromosomal distribution, exon–intron organization, conserved motifs, and collinearity analyses indicated that whole-genome and tandem duplications drove family expansion, with purifying selection as the predominant evolutionary force. Expression profiling across tissues and shoot developmental stages pinpointed DfGDSL58 as the sole highly expressed OsDARX1 homolog in D. farinosus, showing specific upregulation during rapid elongation (50–400 cm). Its promoter contains auxin-responsive elements, and exogenous NAA treatment significantly induced its expression, with a peak at 6 h. Heterologous overexpression of DfGDSL58 (designated DfDACX1) in tobacco increased plant height and basal diameter while reducing lignin and hemicellulose deposition, xylem width, and transcript levels of xylan synthase (NtIRX9) and lignin biosynthetic genes (NtC4H, NtCOMT, NtCAD), whereas cellulose content and cellulose synthase genes (NtCESA4, NtCESA7) remained largely unchanged. Collectively, these findings demonstrate that DfDACX1 negatively regulates secondary wall thickening and promotes longitudinal growth, likely via modulating xylan deacetylation and downstream lignin biosynthesis. This study presents the first systematic characterization of the GDSL family in D. farinosus and identifies DfDACX1 as a key modulator of the trade-off between cell wall deposition and rapid shoot elongation, offering mechanistic insights into bamboo’s extraordinary growth and a potential target for engineering plant architecture. Full article

(This article belongs to the Special Issue Critical Topics in Plant, Algae and Fungi Cell Biology)

► Show Figures

Figure 1

24 pages, 1167 KB

Open AccessReview

Clinical-Cytological Grading in Chronic Rhinosinusitis with Nasal Polyps: An Integrated Framework for Precision Medicine

by Matteo Gelardi

Cells 2026, 15(15), 1426; https://doi.org/10.3390/cells15151426 - 6 Aug 2026

Cited by 1 | Viewed by 568

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease in which type 2 inflammation, epithelial dysfunction, and tissue remodeling determine severity, recurrence, and treatment response. Although molecular biomarkers have clarified disease endotypes, their routine use remains limited by cost, availability, and [...] Read more.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease in which type 2 inflammation, epithelial dysfunction, and tissue remodeling determine severity, recurrence, and treatment response. Although molecular biomarkers have clarified disease endotypes, their routine use remains limited by cost, availability, and invasiveness. Nasal cytology offers a simple, repeatable, and minimally invasive method to assess—at the mucosal surface—both epithelial morphology and the dominant inflammatory infiltrate, whether neutrophilic, eosinophilic, mast cell, or mixed. Clinical-Cytological Grading (CCG) integrates the dominant cytological pattern with selected comorbidities, including asthma, allergy, and NSAID-exacerbated respiratory disease (N-ERD), into a weighted clinical-cytological framework. In the founding cohort, the highest relapse association was observed when mixed eosinophil–mast cell inflammation coexisted with asthma and N-ERD. This review discusses the rationale, clinical relevance, and translational applications of CCG in CRSwNP, addressing eosinophilic and mixed mast cell–eosinophilic inflammation, epithelial morphology, disease recurrence, difficult-to-treat phenotypes, biologic monitoring, and the operative dialogue between nasal cytology and histopathology. By linking cytological findings with selected clinical comorbidities, CCG may support biologically informed patient characterization and may prompt targeted mast cell assessment in tissue. However, its prognostic accuracy, incremental clinical value, and role in therapeutic decision-making require independent external validation. Full article

(This article belongs to the Section Cellular Pathology)

► Show Figures

Figure 1

17 pages, 8507 KB

Open AccessArticle

VdPRMT1 Is Required for Fungal Growth, Metabolism, and Pathogenicity in Verticillium dahliae

by Wenwen Li, Suoxian Li, Siyuan Wu, Xi Jin, Huiming Guo, Hongmei Cheng, Yue Li, Wenfang Guo and Xiaofeng Su

Cells 2026, 15(15), 1425; https://doi.org/10.3390/cells15151425 - 6 Aug 2026

Viewed by 362

Abstract

Protein arginine methyltransferases (PRMTs) are key regulators of diverse cellular processes in eukaryotes, including transcriptional regulation, RNA processing, signal transduction and DNA repair. However, the biological functions of PRMTs in Verticillium dahliae remain largely unexplored. In this study, we identified a PRMT1 homolog [...] Read more.

Protein arginine methyltransferases (PRMTs) are key regulators of diverse cellular processes in eukaryotes, including transcriptional regulation, RNA processing, signal transduction and DNA repair. However, the biological functions of PRMTs in Verticillium dahliae remain largely unexplored. In this study, we identified a PRMT1 homolog in V. dahliae. Targeted deletion of VdPRMT1 resulted in severely impaired hyphal growth, sporulation, stress responses and pathogenicity. Subcellular localization analysis showed that VdPRMT1 is distributed in both the nucleus and cytoplasm of hyphae. Host-induced gene silencing (HIGS) of VdPRMT1 in cotton significantly reduced disease severity, supporting its important role in pathogenicity. Furthermore, VdLuc7, a U1 snRNP-associated protein containing multiple RG/RGG motifs, was identified as a putative interacting partner of VdPRMT1 through yeast two-hybrid (Y2H) screening, bimolecular fluorescence complementation (BiFC) and luciferase complementation imaging (LCI) assays. Together, our results demonstrate that VdPRMT1 is required for normal fungal development and full virulence in V. dahliae, and suggest that arginine methylation may contribute to pathogenicity through regulation of RNA processing-related pathways. These findings provide new insights into the molecular mechanisms underlying fungal virulence and identify VdPRMT1 as a potential target for disease control. Full article

(This article belongs to the Section Plant, Algae and Fungi Cell Biology)

► Show Figures

Graphical abstract

14 pages, 2142 KB

Open AccessArticle

Celiac Disease: Cytokine Profile of Intraepithelial Gamma Delta T Cells in Disease Severity

by Giuseppe Mazzarella, Giuseppe Iacomino, Gaetano Iaquinto, Alessandra Camarca, Errico Picariello, Raffaele Melina and Vera Rotondi Aufiero

Cells 2026, 15(15), 1424; https://doi.org/10.3390/cells15151424 - 6 Aug 2026

Viewed by 1212

Abstract

γδ⁺ intraepithelial lymphocytes (IELs) are persistently expanded in the intestinal epithelium of patients with active celiac disease (ACeD), but their functional profile during active inflammation remains poorly defined. This study investigated the expression of pro- and anti-inflammatory cytokines in γδ⁺ IELs [...] Read more.

γδ⁺ intraepithelial lymphocytes (IELs) are persistently expanded in the intestinal epithelium of patients with active celiac disease (ACeD), but their functional profile during active inflammation remains poorly defined. This study investigated the expression of pro- and anti-inflammatory cytokines in γδ⁺ IELs isolated from the intestinal epithelium of ACeD patients at different stages of mucosal damage. Frozen jejunum sections were obtained from 14 ACeD patients (7 Marsh II and 7 Marsh III) and 10 treated celiac disease (CeD) patients. γδ⁺ IELs from ACeD biopsies and intestinal enterocytes (IEs) from treated CeD biopsies were isolated by laser capture microdissection on mirror sections, followed by RNA extraction and quantitative real-time RT-PCR analysis of IL-15, IL-17A, IL-21, IFN-γ, TNF-α, IL-10, and TGF-β. Foxp3 expression was assessed by immunohistochemistry. γδ⁺ IELs from Marsh III biopsies showed significantly increased mRNA levels of IL-15, IL-17A, IL-21, IFN-γ, and TGF-β compared with IEs, whereas IL-10 expression was significantly higher in Marsh II γδ⁺ IELs compared with Marsh III and IEs. IL-21 and TGF-β were also higher in Marsh III than Marsh II γδ⁺ IELs. All γδ⁺ IELs were Foxp3⁻. These findings indicate a stage-dependent functional polarization of γδ⁺ IELs in ACeD, with an IL-10–associated regulatory profile in Marsh II and a predominant pro-inflammatory cytokine signature in Marsh III. Full article

(This article belongs to the Section Cellular Immunology)

► Show Figures

Graphical abstract

21 pages, 3600 KB

Open AccessProtocol

Isolation and Purification of Mast Cells from Murine Colonic Mucosa

by Ana M. Estepa-San Nicolás, Laura E. Córdova-Dávalos, Eduardo E. Valdez-Morales, Daniel Cervantes-García, Mariela Jiménez, Jesús Barrera-Juárez, Guillermo A. Cabral-García, Claudia González-Espinosa, Raquel Guerrero-Alba and Eva Salinas

Cells 2026, 15(15), 1423; https://doi.org/10.3390/cells15151423 - 6 Aug 2026

Viewed by 449

Abstract

Mast cells (MCs) are immune cells that produce numerous immunological mediators involved in inflammatory and allergic responses. Increased numbers of MCs are observed in chronic inflammatory reactions in organs such as the colon. There, MCs seem to participate in deleterious immune responses and [...] Read more.

Mast cells (MCs) are immune cells that produce numerous immunological mediators involved in inflammatory and allergic responses. Increased numbers of MCs are observed in chronic inflammatory reactions in organs such as the colon. There, MCs seem to participate in deleterious immune responses and tissue damage, but the detailed mechanisms of their activation are not known, mostly because procedures to obtain MC primary cultures from the colonic mucosa are expensive and time-consuming and present low yield. Here we describe a protocol to obtain MCs from the colonic mucosa (cmMCs) of C57BL/6 mice with high yield, viability and purity. Mucosal colon cells were dispersed by enzymatic digestion, and cmMCs were isolated by Percoll continuous-gradient centrifugation. This method allowed for the purification of 1,446,667 ± 112,442 cell/g of mucosal tissue, with 87.22% viability and 95.16% purity. The mucosal-like phenotype was predominant in isolated cmMCs, characterized by weak toluidine blue staining but strong expression of MC protease-1 (Mcpt1). Activation assays showed that freshly isolated cmMCs increased intracellular calcium and showed degranulation in response to ATP or IgE-antigen-dependent FcεRI cross-linking. This highly reproducible technique is cost-effective and requires no specialized equipment. This protocol could be applied in research related to inflammatory bowel disease, colon cancer or food allergies. Full article

(This article belongs to the Section Cell Methods)

► Show Figures

Graphical abstract

39 pages, 13353 KB

Open AccessReview

Metabolic Bottlenecks and Opportunities: Reshaping the Tumor Microenvironment for Cancer Immunotherapy

by Jianing Zhang, Zimei Tang, Yiran Wang, Jiaying Wan, Yajing Zhou, Jiexiao Li and Jie Ming

Cells 2026, 15(15), 1422; https://doi.org/10.3390/cells15151422 - 5 Aug 2026

Viewed by 1175

Abstract

Metabolic reprogramming constitutes a fundamental hallmark of malignancy, orchestrating a hostile tumor microenvironment (TME) that severely compromises anti-tumor immunity. Despite the transformative success of immune checkpoint blockade and adoptive cell therapies, clinical efficacy is frequently curtailed by the metabolic barriers imposed by the [...] Read more.

Metabolic reprogramming constitutes a fundamental hallmark of malignancy, orchestrating a hostile tumor microenvironment (TME) that severely compromises anti-tumor immunity. Despite the transformative success of immune checkpoint blockade and adoptive cell therapies, clinical efficacy is frequently curtailed by the metabolic barriers imposed by the TME. This review systematically elucidates the complex metabolic interplay between tumor cells and infiltrating T cells, highlighting two defining mechanisms driving immune evasion: the competitive sequestration of essential nutrients and the accumulation of immunosuppressive oncometabolites. We detail how the depletion of glucose and critical amino acids (glutamine, arginine, methionine, etc.) imposes a state of “metabolic siege” on T cells, impairing their bioenergetics and effector functions. Concurrently, we explore how accumulated metabolites—such as lactate, succinate, 2-hydroxyglutarate, kynurenine, and lipids—function as non-canonical signaling molecules to subvert immune surveillance via epigenetic remodeling and oxidative stress. Furthermore, we synthesize emerging therapeutic strategies designed to dismantle this metabolic barrier, including targeting metabolic enzymes (IDO1 and FASN) and transporters, repurposing metabolic waste, and genetically engineering T cells with enhanced metabolic fitness and resilience. By integrating the latest insights into the “metabolism–epigenetics–immunity” axis, this review provides a theoretical foundation for developing next-generation immunotherapies that target metabolic vulnerabilities to overcome resistance in cancer treatment. Full article

(This article belongs to the Topic The Tumor Microenvironment, Immuno-Oncology, and Immune Checkpoint: Implications for Current and Emergent Immunotherapies, 2nd Edition)

► Show Figures

Figure 1

42 pages, 4086 KB

Open AccessReview

From Metal Stress to Regulated Cell Death: An Evidence Framework for Ferroptosis–Cuproptosis Crosstalk in Cancer

by Andrada-Adelaida Belbe, Lorin-Manuel Pîrlog, Andrei Sporiș, Adela-Diana Pitforodeschi, Alissia-Nicoleta Pilatec, Rareș-Mihai Băilă, Irina Rusu, Mihaela Amelia Dobrescu, Mariela-Sanda Militaru, Irina-Ioana Iordănescu and Andreea Cătană

Cells 2026, 15(15), 1421; https://doi.org/10.3390/cells15151421 - 5 Aug 2026

Viewed by 841

Abstract

Resistance to apoptosis, metabolic plasticity, and redox adaptation are major contributors to cancer progression and treatment failure. Ferroptosis and cuproptosis have therefore emerged as metal-dependent forms of regulated cell-death programs with potential relevance for tumours that survive conventional therapy. Ferroptosis is driven by [...] Read more.

Resistance to apoptosis, metabolic plasticity, and redox adaptation are major contributors to cancer progression and treatment failure. Ferroptosis and cuproptosis have therefore emerged as metal-dependent forms of regulated cell-death programs with potential relevance for tumours that survive conventional therapy. Ferroptosis is driven by iron-dependent phospholipid peroxidation when glutathione peroxidase 4 (GPX4)-dependent and parallel antioxidant systems fail, whereas cuproptosis depends on mitochondrial copper engagement of lipoylated tricarboxylic-acid-cycle proteins, lipoylated-protein aggregation, iron–sulfur protein destabilization, and proteotoxic stress. This review integrates the molecular basis, genetic architecture, long non-coding RNA (lncRNA)-mediated regulation, mechanistic crosstalk, and therapeutic implications of ferroptosis and cuproptosis in cancer. It emphasizes a critical evidence hierarchy: expression association, computational signature construction, metal accumulation, reactive oxygen species (ROS) generation, or reduced viability should not be interpreted as pathway dependency without pathway-defining biochemical endpoints and rescue experiments. The most credible translational opportunities will depend on functional stratification, tumour-selective delivery, and pharmacodynamic confirmation that distinguishes pathway-defined ferroptosis or cuproptosis from nonspecific metal-induced and oxidative cytotoxicity. Full article

► Show Figures

Figure 1

34 pages, 21892 KB

Open AccessArticle

Valorization of Paris polyphylla Byproducts: Integrated Multi-Omics and Molecular Docking Reveal the Anti-Melanogenic Mechanism of Plant-Derived Nanovesicles via the AKT/GSK3β/MITF Axis

by Peishi Feng, Li Tao, Xiaoli Chen, Han Yang, Yida Zhang and Ping Wang

Cells 2026, 15(15), 1420; https://doi.org/10.3390/cells15151420 - 5 Aug 2026

Viewed by 647

Abstract

Valorizing agricultural byproducts into functional ingredients is highly desirable. Herein, plant-derived nanovesicles (PDNVs) from Paris polyphylla stems/leaves (SL-EXO) exhibited potent anti-melanogenic properties, whereas root-derived PDNVs were ineffective. In vitro, SL-EXO achieved 92.66% cell-free tyrosinase inhibition, while α-arbutin was 49.78%. In vivo, SL-EXO ameliorated [...] Read more.

Valorizing agricultural byproducts into functional ingredients is highly desirable. Herein, plant-derived nanovesicles (PDNVs) from Paris polyphylla stems/leaves (SL-EXO) exhibited potent anti-melanogenic properties, whereas root-derived PDNVs were ineffective. In vitro, SL-EXO achieved 92.66% cell-free tyrosinase inhibition, while α-arbutin was 49.78%. In vivo, SL-EXO ameliorated the pigmentation-driving oxidative/senescent microenvironment in zebrafish and reduced macroscopic melanin by ~66%. Crucially, SL-EXO reversed α-MSH-induced hyperpigmentation in B16F10 cells while maintaining excellent biocompatibility up to 0.15 mg/mL, displaying a vastly superior safety margin compared to α-arbutin (which induced cytotoxicity at 0.075 mg/mL). To decode this, multi-omics profiling revealed that SL-EXO utilizes a chloroplast-derived biomimetic lipid architecture (enriched in MGDG/DGDG) to efficiently deliver potent flavonoid payloads. Molecular docking demonstrated exceptional predictive structural affinities (binding energies up to −10.9 kcal/mol) between these phytochemicals and AKT1. Finally, pharmacological rescue assays validated that SL-EXO arrests melanogenesis by targeting the AKT1 pathway, thereby downregulating the p-AKT/p-GSK3/MITF signaling cascade and silencing melanogenic genes. This study establishes a rigorous multi-omics paradigm for upcycling botanical wastes into exceptionally safe and efficacious natural anti-melanogenic nanotherapeutics. Full article

(This article belongs to the Special Issue Cellular and Molecular Research of Plant-Derived Exosomes)

► Show Figures

Graphical abstract

35 pages, 6941 KB

Open AccessArticle

Rosmarinic Acid Potentiates Cisplatin-Induced Antitumour Activity Through ROS-Associated Apoptotic Signalling in Two- and Three-Dimensional Breast Cancer Models

by Coşkun Orhaner, Aylin Orhaner, Mehmet Cudi Tuncer and İlhan Özdemir

Cells 2026, 15(15), 1419; https://doi.org/10.3390/cells15151419 - 5 Aug 2026

Viewed by 478

Abstract

Triple-negative breast cancer (TNBC) remains a highly aggressive malignancy with limited therapeutic options and frequent resistance to platinum-based chemotherapy. Rosmarinic acid (RA), a naturally occurring polyphenol, has attracted considerable interest as a potential chemosensitising agent. This study investigated the anticancer activity and the [...] Read more.

Triple-negative breast cancer (TNBC) remains a highly aggressive malignancy with limited therapeutic options and frequent resistance to platinum-based chemotherapy. Rosmarinic acid (RA), a naturally occurring polyphenol, has attracted considerable interest as a potential chemosensitising agent. This study investigated the anticancer activity and the underlying mechanisms of RA combined with cisplatin (CDDP) in 4T1 breast cancer cells while assessing the cytotoxic responses of non-cancerous HaCaT keratinocytes as a preliminary indicator of differential treatment sensitivity. Cytotoxicity was assessed using the MTT assay, followed by calculation of the Combination Index (CI), Drug Reduction Index (DRI), and Selectivity Index (SI). The generation of intracellular reactive oxygen species (ROS) was evaluated by DCFH-DA fluorescence imaging, and the functional contribution of oxidative stress was examined using N-acetyl-L-cysteine (NAC) rescue experiments. Apoptosis was analysed by Annexin V/PI flow cytometry, NucBlue nuclear staining, and Calcein-AM/propidium iodide (PI) Live/Dead fluorescence imaging. Three-dimensional (3D) tumour spheroids were used to assess treatment-induced alterations in spheroid morphology, morphometric parameters, viability based on adenosine triphosphate (ATP), and Live/Dead staining. The expression of genes related to apoptosis was determined by RT-qPCR, and potential molecular mechanisms were explored using the construction of protein–protein interaction (PPI) networks together with Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses. The combination of RA + CDDP exhibited strong synergistic cytotoxicity in 4T1 cells while demonstrating comparatively lower toxicity toward HaCaT keratinocytes. Combination treatment markedly increased intracellular ROS generation, whereas NAC significantly reduced ROS accumulation and partially restored cell viability, indicating that oxidative stress is a major but not exclusive mediator of cytotoxicity. Combined treatment significantly enhanced apoptotic cell death, increased chromatin condensation and membrane damage, upregulated the expression of Bax, Casp9, Cycs, and Trp53, and downregulated Bcl2, consistent with transcriptional regulation of intrinsic apoptotic signalling. In 3D tumour spheroids, the combination markedly reduced spheroid size, disrupted structural integrity, decreased ATP-based viability, and substantially increased tumour cell death compared to monotherapy. Bioinformatic analyses identified central genes related to apoptosis and cell survival and predicted significant enrichment of PI3K/Akt, p53, MAPK, and apoptosis signalling pathways. RA significantly potentiates the antitumor efficacy of CDDP through synergistic induction of ROS-associated apoptotic signalling while showing a more favourable cytotoxic response in 4T1 breast cancer cells than in non-cancerous HaCaT keratinocytes. The integrated findings from two-dimensional (2D) and 3D models, NAC rescue experiments, molecular analyses, and bioinformatics collectively support the potential of RA as a promising chemosensitising adjuvant for CDDP-based breast cancer therapy and warrant further validation in preclinical in vivo models. Full article

(This article belongs to the Special Issue New Insights into Plant Bioactive Compounds)

► Show Figures

Graphical abstract

11 pages, 2650 KB

Open AccessArticle

Expression Defects of SCN5A Common Polymorphisms S524Y and H558R in the Q1077 Splice Variant Can Be Rescued by Mexiletine

by Rou-Mu Hu, Evelyn J. Song, Carmen R. Valdivia, Isabelle Deschenes, Jonathan C. Makielski and Bi-Hua Tan

Cells 2026, 15(15), 1418; https://doi.org/10.3390/cells15151418 - 5 Aug 2026

Viewed by 439

Abstract

The cardiac sodium channel Na_V1.5, encoded by SCN5A, generates the inward sodium current required for myocardial excitability and impulse conduction. Loss-of-function mutations of Na_V1.5 have been implicated in inherited arrhythmia syndromes, including Brugada syndrome, progressive cardiac conduction disease, and [...] Read more.

The cardiac sodium channel Na_V1.5, encoded by SCN5A, generates the inward sodium current required for myocardial excitability and impulse conduction. Loss-of-function mutations of Na_V1.5 have been implicated in inherited arrhythmia syndromes, including Brugada syndrome, progressive cardiac conduction disease, and congenital sick sinus syndrome. The common SCN5A polymorphism H558R has reported minor allele frequencies ranging from 9.2% to 29% across ethnic groups, whereas S524Y has been described in individuals of African ancestry with a minor allele frequency of approximately 3.3%. Two splice variants of human SCN5A, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077, exist in every human in a 2:1 mRNA transcript ratio. We engineered these two polymorphisms in both backgrounds and reported that when S524Y and H558R were expressed in the Q1077del variant, current densities were normal. In the Q1077 variant, however, the current densities showed a dramatic reduction compared to those in the Q1077del variant or WT-Q1077. We previously reported that incubation with the antiarrhythmic drug mexiletine “rescued” expression deficiencies in the Brugada syndrome. Cells expressing S524Y/Q1077 and H558R/Q1077 were incubated for 48 h with or without mexiletine (500 μM), followed by drug washout before electrophysiological assessment. Mexiletine significantly increased current density for both S524Y/Q1077 and H558R/Q1077 compared with untreated cells, restoring current density to levels comparable to WT-Q1077. Flow cytometry using a FLAG-tagged channel demonstrated that mexiletine-mediated rescue was associated with increased cell-surface expression. The magnitude of the expression defects caused by H558R and S524Y in the Q1077 splice background is similar to that observed with arrhythmia-associated SCN5A mutations, and we show for the first time that the defects for both polymorphisms can be rescued with mexiletine. Although it is unknown whether they result in heightened arrhythmia susceptibility in patients homozygous for the minor allele, our result may have implications for therapy for mutations with loss-of-function phenotypes modified by these common polymorphisms. Full article

(This article belongs to the Special Issue Advances in Ion Channel Biology: From Molecular Mechanisms to Therapeutic Targets)

► Show Figures

Figure 1

23 pages, 14603 KB

Open AccessArticle

Graphene Oxide Modulates ROS Production and Apoptotic Responses to Bortezomib in Human Glioblastoma Cells: An In Vitro Study

by Rafał Krętowski, Agata Jabłońska-Trypuć, Natalia Tyszka, Joanna Kalita and Marzanna Cechowska-Pasko

Cells 2026, 15(15), 1417; https://doi.org/10.3390/cells15151417 - 5 Aug 2026

Viewed by 467

Abstract

Glioblastoma multiforme (GBM) remains one of the most aggressive and treatment-resistant brain tumors, characterized by rapid proliferation and poor patient prognosis. Novel therapeutic strategies are urgently needed to improve clinical outcomes. In this study, we investigated the cytotoxic and pro-apoptotic effects of bortezomib [...] Read more.

Glioblastoma multiforme (GBM) remains one of the most aggressive and treatment-resistant brain tumors, characterized by rapid proliferation and poor patient prognosis. Novel therapeutic strategies are urgently needed to improve clinical outcomes. In this study, we investigated the cytotoxic and pro-apoptotic effects of bortezomib (BORT), a proteasome inhibitor, and graphene oxide (GO), a nanomaterial with known anticancer potential, on human glioblastoma cell lines. Treatment with BORT and GO, both individually and in combination, significantly reduced cell viability in a dose-dependent manner, as determined by MTT. In this study, we observed enhanced apoptotic cell death, accompanied by increased activation of both caspase-8 and caspase-9, indicating simultaneous engagement of extrinsic and intrinsic apoptotic pathways. Western blot analysis demonstrated downregulation of anti-apoptotic proteins Bcl-2 and upregulation of pro-apoptotic markers (NOXA, cleaved PARP). A central finding of this work is the pronounced increase in intracellular reactive oxygen species (ROS) levels following BORT–GO treatment. The elevated ROS levels observed in BORT–GO-treated cells compared with free bortezomib therefore suggest that GO-mediated oxidative stress may amplify proteasome inhibition-induced apoptosis, which is particularly visible in the A172 and LN229 cell lines. Notably, the combination of BORT and GO may suggest a potential cooperative mechanism through proteasome inhibition and oxidative stress induction. These findings indicate that graphene oxide may modulate the antitumor efficacy of bortezomib in a cell line-dependent manner and support further investigation of this combination as a promising therapeutic approach for glioblastoma. Full article

(This article belongs to the Special Issue Cell Death Mechanisms and Therapeutic Opportunities in Glioblastoma)

► Show Figures

Figure 1

26 pages, 2635 KB

Open AccessReview

Mechanisms and Translational Potential of Plant-Derived Extracellular Vesicles in Cardiovascular Disease

by Songyan Tie, Huifang Kuang, Hang Xu, Qian Guo, Jie Li and Lingli Chen

Cells 2026, 15(15), 1416; https://doi.org/10.3390/cells15151416 - 5 Aug 2026

Viewed by 627

Abstract

Cardiovascular diseases remain a major global health burden. Plant-derived extracellular vesicles (PDEVs) are increasingly being investigated as potential therapeutic and drug-delivery platforms for cardiovascular disease. PDEVs are natural nanovesicles carrying bioactive lipids, proteins, nucleic acids, and phytochemicals. Preclinical studies suggest that selected PDEV [...] Read more.

Cardiovascular diseases remain a major global health burden. Plant-derived extracellular vesicles (PDEVs) are increasingly being investigated as potential therapeutic and drug-delivery platforms for cardiovascular disease. PDEVs are natural nanovesicles carrying bioactive lipids, proteins, nucleic acids, and phytochemicals. Preclinical studies suggest that selected PDEV preparations may exert protective effects in cardiovascular disease-related models by modulating inflammation, oxidative stress, lipid metabolism, and endothelial repair. In experimental models, selected PDEVs have shown preliminary improvements in cargo stability, lesion accumulation, controlled release, and local retention through drug loading, surface ligand modification, responsive design, and integration with biomaterials. This review summarises the biogenesis, isolation, characterisation, and cardiovascular actions of PDEVs, with emphasis on their engineering and targeted delivery applications in atherosclerosis, myocardial infarction, ischaemia–reperfusion injury, vascular calcification, restenosis, and cardiotoxicity. Current challenges, including insufficient standardization, uncertain regulatory classification, unclear mechanisms, and limited pharmacokinetic and long-term safety data, are also discussed. Addressing these issues is essential for reliably evaluating the clinical translation potential of PDEVs. Full article

(This article belongs to the Special Issue Cellular and Molecular Research of Plant-Derived Exosomes)

► Show Figures

Figure 1

28 pages, 1648 KB

Open AccessArticle

Altered Mitochondrial Base Excision Repair and Mitochondrial DNA Instability in Peripheral Leukocytes of Patients with MASLD

by Sylwia Ziółkowska, Marcin Kosmalski, Bianka Świderska, Agnieszka Szczypiorowska, Kinga Jarmusz, Magdalena Ejsmont, Adam Marek Wróblewski, Janusz Szemraj, Tadeusz Pietras, Aleksandra Jabłkowska and Piotr Czarny

Cells 2026, 15(15), 1415; https://doi.org/10.3390/cells15151415 - 5 Aug 2026

Viewed by 593

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial metabolic disorder that is strongly associated with mitochondrial dysfunction and oxidative stress, which may potentially compromise the integrity of mitochondrial DNA (mtDNA). However, the role of the base excision repair (BER) pathway—the main mechanism [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial metabolic disorder that is strongly associated with mitochondrial dysfunction and oxidative stress, which may potentially compromise the integrity of mitochondrial DNA (mtDNA). However, the role of the base excision repair (BER) pathway—the main mechanism responsible for repairing oxidative lesions in mitochondria—and maintaining mtDNA stability in MASLD remains poorly understood. Here, we analyzed total mRNA expression levels of key BER components in whole-blood samples, along with mitochondrial protein levels of the selected components. Additionally, we assessed the mtDNA copy number and the damage of mtDNA and nuclear DNA in peripheral leukocytes from MASLD patients and healthy controls. We found that MASLD patients differed from controls in mtDNA and nuclear DNA damage, mtDNA copy number, and selected BER-related markers. However, because the MASLD and control groups also differed substantially in age and BMI, these molecular differences should be interpreted as potentially being associated with age- and BMI-related metabolic status rather than attributable to MASLD alone. While several BER-related genes were downregulated at the mRNA level, the corresponding mitochondrial protein levels were not consistently decreased in MASLD (ProteomeXchange: PXD075974), indicating a discordance between transcriptional and protein-level regulation. These results suggest that altered mitochondrial BER and mtDNA instability in peripheral leukocytes may reflect the combined influence of MASLD, aging, obesity, and broader metabolic dysfunction. Full article

(This article belongs to the Special Issue Advances in Metabolic Dysfunction-Associated Steatotic Liver Disease)

► Show Figures

Graphical abstract

29 pages, 18420 KB

Open AccessArticle

Integrated Multi-Omics and Interactome Analysis of CDK8 Inhibition Reveals Erythroid Differentiation Programs and Therapeutic Synergy with BET Blockade in AML

by Malgorzata Statkiewicz, Izabela Rumienczyk, Urszula Pakulska, Marta Obacz, Maria Kulecka, Jarosław Cendrowski, Magdalena Cubulska-Lubak, Ewelina Kaniuga, Zuzanna Sandowska-Markiewicz, Wioletta Slusarczyk-Kacprzyk, Krzysztof Goryca, Tymon Rubel, Magdalena Bakun, Bianka Swiderska, Kamila Kruczkowska-Tarantowicz, Piotr Rzepecki, Jolanta Korsak, Krystyna Kyc-Wachowiak, Anna Polak, Przemyslaw Juszczynski, Milena Mazan, Tomasz Rzymski, Jerzy Ostrowski and Michal Mikula Show full author list Hide full author list

Cells 2026, 15(15), 1414; https://doi.org/10.3390/cells15151414 - 4 Aug 2026

Viewed by 792

Abstract

Acute myeloid leukaemia (AML) is a therapeutically challenging malignancy driven by the self-renewal, quiescence, and therapy resistance of leukaemic stem cells (LSCs). CDK8, a kinase component of the Mediator complex, regulates oncogenic transcription, and the selective CDK8/CDK19 inhibitor RVU120 (Romaciclib) targets AML cells [...] Read more.

Acute myeloid leukaemia (AML) is a therapeutically challenging malignancy driven by the self-renewal, quiescence, and therapy resistance of leukaemic stem cells (LSCs). CDK8, a kinase component of the Mediator complex, regulates oncogenic transcription, and the selective CDK8/CDK19 inhibitor RVU120 (Romaciclib) targets AML cells with CD34⁺/pSTAT5-high LSC-like characteristics; however, the epigenetic and transcriptional consequences of CDK8 blockade and actionable combinatorial strategies remain incompletely defined. Using the TEX cell line, an LSC-enriched surrogate model, we performed time-resolved RNA-seq, whole-proteome and phosphoproteomics mass spectrometry (MS), and CUT&Tag chromatin profiling following treatment with RVU120 and CCT251921. CDK8 protein–protein interactions were mapped by co-immunoprecipitation MS across five AML models, and synergy with Pelabresib (BET inhibitor) or CB6644 (RUVBL1/2 inhibitor) was assessed by high-content screening in three cell lines and three patient-derived xenograft (PDX) models. Both inhibitors suppressed STAT5 phosphorylation, induced loss of the CD34⁺/CD38⁻ LSC-enriched phenotype, and drove erythromegakaryocytic differentiation. Transcriptomic and proteomic responses were concordant, and CDK8 inhibition triggered widespread enhancer activation with redistribution of RNAP2, BRD3, and NFRKB. CDK8 combined with Pelabresib acted synergistically in MOLM-16 cells and two of three PDX models. These findings identify CDK8 as a transcriptional node of LSC-associated programs and provide a mechanistic rationale for combined CDK8-BET inhibition in molecularly defined AML subsets, which will require validation in functional LSC assays and primary specimens. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: Unraveling Molecular Drivers, Cellular Plasticity, and Therapeutic Vulnerabilities)

► Show Figures

Graphical abstract

20 pages, 3156 KB

Open AccessReview

Vesicular Communication in the Bone–Muscle Unit: Physiological Functions, Aging, and Therapeutic Potential

by Virginia Veronica Visconti, Chiara Greggi, Antonio Matticari, Riccardo Iundusi, Elena Gasbarra, Annalisa Botta and Umberto Tarantino

Cells 2026, 15(15), 1413; https://doi.org/10.3390/cells15151413 - 4 Aug 2026

Viewed by 660

Abstract

Extracellular vesicles (EVs) have emerged as fundamental pillars of intercellular communication, acting as primary mediators of the bidirectional biochemical crosstalk within the integrated bone–muscle unit. This review provides a comprehensive synthesis of EV-mediated signaling across the bone–muscle axis, offering a side-by-side mapping of [...] Read more.

Extracellular vesicles (EVs) have emerged as fundamental pillars of intercellular communication, acting as primary mediators of the bidirectional biochemical crosstalk within the integrated bone–muscle unit. This review provides a comprehensive synthesis of EV-mediated signaling across the bone–muscle axis, offering a side-by-side mapping of vesicular biogenesis, cargo composition, and functional roles in both tissues. Under physiological conditions, skeletal muscle- and bone-derived EVs orchestrate tissue homeostasis, adaptations to physical exercise, myogenesis, and bone remodeling by transferring unique molecular cargos of proteins and specific microRNAs. However, aging induces a profound remodeling of the EV secretome toward a senescent profile characterized by harmful vesicular factors. This dysfunctional vesicular signaling impairs both muscle regeneration and osteogenesis, directly contributing to the pathogenesis of interconnected age-related disorders like sarcopenia, osteoporosis, and osteosarcopenia. Concurrently, circulating EVs represent valuable, minimally invasive biomarkers for early diagnosis. On the therapeutic front, this review critically evaluates emerging EV-based approaches, utilizing mesenchymal stem cell-derived, bioengineered, or biomaterial-incorporated EVs, offering promising, low-immunogenic alternatives to cell transplantation to enhance musculoskeletal tissue repair and restore bone–muscle homeostasis. Despite persisting technical challenges regarding large-scale production and standardization, targeting or leveraging EV-mediated communication represents one of the most innovative and revolutionary strategies to counteract age-related musculoskeletal decline. By unifying physiological mechanisms, age-related molecular reprogramming, and therapeutic engineering across both muscle and bone into a single narrative, this review provides a comprehensive framework to guide future research and clinical translation in musculoskeletal health. Full article

(This article belongs to the Special Issue Molecular Research in Osteoporosis)

► Show Figures

Graphical abstract

28 pages, 1654 KB

Open AccessReview

Macrophages and the Tissue Repair Circuit: Homeostasis, Autoimmune Diseases, and Resolution-Based Therapeutic Strategies

by Kenta Mosallanejad, Cedric Hubeau, Annette Schwartz Sterman and Yunhao Tan

Cells 2026, 15(15), 1412; https://doi.org/10.3390/cells15151412 - 4 Aug 2026

Viewed by 1188

Abstract

Tissue repair and regeneration are highly coordinated multicellular processes that rely on the active resolution of inflammation rather than merely its passive cessation. Reciprocal orchestration among stromal, innate, and adaptive immune systems is key to maintaining or restoring tissue homeostasis from pathological perturbations. [...] Read more.

Tissue repair and regeneration are highly coordinated multicellular processes that rely on the active resolution of inflammation rather than merely its passive cessation. Reciprocal orchestration among stromal, innate, and adaptive immune systems is key to maintaining or restoring tissue homeostasis from pathological perturbations. Macrophages serve as a central nexus of these responses, exhibiting dynamic functional plasticity that extends beyond dichotomous M1/M2 classification. This review explores the evolving, context-dependent roles of macrophages in restoring tissue homeostasis, with a particular focus on efferocytosis and subsequent metabolic rewiring as key drivers of inflammation resolution. Furthermore, we highlight the bi-directional crosstalk between macrophages and heterogeneous fibroblast populations. While these stromal-myeloid interactions are essential for transient matrix remodeling and physiological healing, their sustained activation under inflammatory conditions drives maladaptive repair and fibrotic remodeling. We discuss how the defects and dysregulation of these cellular circuits contribute to the pathogenesis of autoimmune disorders, as exemplified by recent findings in rheumatoid arthritis (RA), systemic sclerosis (SSc), and inflammatory bowel disease (IBD). Finally, we evaluate emerging “resolution therapies” that aim to harness endogenous tissue-reparative programs of macrophages therapeutically to treat autoimmune diseases, including the application of specialized pro-resolving mediators (SPMs) and macrophage reprogramming strategies. Full article

(This article belongs to the Special Issue Role of Macrophages in Tissue Repair)

► Show Figures

Figure 1

25 pages, 5666 KB

Open AccessReview

Autophagy at the Crossroads of Protein and RNA Toxicity in Repeat Expansion Cerebellar Ataxias

by Silvia Tortoriello, Simona Rossi, Ilaria Della Valle, Nadia D’Ambrosi and Mauro Cozzolino

Cells 2026, 15(15), 1411; https://doi.org/10.3390/cells15151411 - 4 Aug 2026

Viewed by 558

Abstract

Repeat expansion cerebellar ataxias comprise a genetically and mechanistically heterogeneous group of neurodegenerative disorders unified by the pathological expansion of short tandem repeats (STRs) beyond a disease-causing threshold. Depending on their genomic localization, these expansions can lead to toxic protein gain-of-function, as in [...] Read more.

Repeat expansion cerebellar ataxias comprise a genetically and mechanistically heterogeneous group of neurodegenerative disorders unified by the pathological expansion of short tandem repeats (STRs) beyond a disease-causing threshold. Depending on their genomic localization, these expansions can lead to toxic protein gain-of-function, as in polyglutamine (polyQ) cerebellar ataxias, or to RNA-mediated toxicity and repeat-associated non-AUG (RAN) translation, for which recent evidence supports a major pathogenic role in non-coding spinocerebellar ataxias (SCAs). Despite these distinct upstream mechanisms, disruption of neuronal homeostasis occurs through converging pathogenic processes, including proteostasis impairment, transcriptional dysregulation, and mitochondrial dysfunction, leading to progressive neuronal loss. Importantly, impaired autophagy has been consistently reported across multiple repeat expansion ataxias, including both dominant SCAs and recessive conditions, such as Friedreich’s ataxia, suggesting that impairment of this pathway may represent a shared downstream event in disease progression. Indeed, in polyQ cerebella ataxias, the accumulation of misfolded and aggregation-prone proteins places a substantial burden on cellular quality control systems, particularly the ubiquitin-proteasome system and autophagy. Similarly, in non-coding SCAs, toxic RNA species and RAN-derived peptides might interfere with protein clearance mechanisms and contribute to cellular stress. In this review, we will discuss the evidence supporting autophagy impairment as a convergent pathogenic pathway in repeat expansion cerebellar ataxias. Full article

► Show Figures

Figure 1

12 pages, 464 KB

Open AccessReview

Intra-Articular Monoclonal Antibodies in Temporomandibular Joint Disorders: Current Evidence

by Zuzanna Baniak, Maciej Chęciński, Wojciech Macek, Maja Kosińska, Amelia Hoppe, Julia Kasprzycka, Oliwia Jagiełło, Izabella Chyży, Karolina Grzybowska-Kowalczyk, Tomasz Horodniczy, Kamila Chęcińska and Maciej Sikora

Cells 2026, 15(15), 1410; https://doi.org/10.3390/cells15151410 - 4 Aug 2026

Viewed by 410

Abstract

Immune-mediated temporomandibular joint disorders involve cytokine-driven inflammation and may represent a target for biologic therapy. This paper summarizes the evidence on intra-articular monoclonal antibody administration in temporomandibular joint disorders. PubMed, Europe PMC, and BASE were searched from inception to 7 April 2026 for [...] Read more.

Immune-mediated temporomandibular joint disorders involve cytokine-driven inflammation and may represent a target for biologic therapy. This paper summarizes the evidence on intra-articular monoclonal antibody administration in temporomandibular joint disorders. PubMed, Europe PMC, and BASE were searched from inception to 7 April 2026 for clinical and preclinical studies evaluating intra-articular monoclonal antibodies in the temporomandibular joint. Four studies were identified: two retrospective clinical studies, one case report, and one preclinical study. All four studies investigated local TNF-α blockade: the three clinical studies used infliximab, whereas the preclinical study used an anti-rabbit TNF-α monoclonal antibody. Symptomatic benefit was confined to one adult case and anti-inflammatory effects to the preclinical study, whereas pediatric MRI abnormalities persisted or worsened, providing no evidence of structural efficacy. The evidence remains limited, heterogeneous, and exploratory. Intra-articular monoclonal antibody therapy is biologically plausible, but its clinical efficacy and safety require further investigation. Full article

(This article belongs to the Special Issue The Role of T Cells and Cellular Signalling in Immune Diseases)

► Show Figures

Figure A1

13 pages, 1658 KB

Open AccessArticle

Protective Role of Donor KIR B Haplotype in Cytomegalovirus Reactivation Following T-Cell-Depleted Hematopoietic Stem Cell Transplantation

by Rehan M. Faridi, Nazanin Vaziri, Mohammad Saad Husain, Poonam Dharmani-Khan, Amit Kalra, Noureddine Berka, Jan Storek and Faisal M. Khan

Cells 2026, 15(15), 1409; https://doi.org/10.3390/cells15151409 - 4 Aug 2026

Viewed by 444

Abstract

Background: Cytomegalovirus (CMV) reactivation is a major complication after hematopoietic stem cell transplantation (HSCT). Natural killer (NK) cells help control CMV through killer-cell immunoglobulin-like receptors (KIRs) and their HLA ligands, but donor-derived CMV-specific T-cells may confound the interpretation of NK-mediated effects. Methods [...] Read more.

Background: Cytomegalovirus (CMV) reactivation is a major complication after hematopoietic stem cell transplantation (HSCT). Natural killer (NK) cells help control CMV through killer-cell immunoglobulin-like receptors (KIRs) and their HLA ligands, but donor-derived CMV-specific T-cells may confound the interpretation of NK-mediated effects. Methods: We analyzed 276 HLA-matched (10/10) adults receiving ATG-based T-cell-depleted myeloablative HSCT with a known donor and recipient CMV serostatus. The donor and recipient KIR genotypes were scored by the Cooley B-content score (0–4; ≥2 = high). Clinically significant CMV reactivation (plasma viral load > 25,000 IU/mL, the institutional threshold for pre-emptive therapy) was analyzed with Fine–Gray competing-risks regression, stratified by the donor–recipient serostatus. Results: In seronegative-donor/seropositive-recipient (D−R+) pairs (n = 68), a high donor KIR B-content score was associated with a significantly lower reactivation risk (sub-hazard ratio, 0.46; 95% CI, 0.24–0.91; p = 0.024). No effect was seen in D+R+ pairs (n = 82; SHR, 0.65; p = 0.241); D+R− (n = 28) had too few events to model. A donor Tel-AA/recipient Tel-B+ mismatch was independently associated with a higher reactivation risk (adjusted HR, 2.41; 95% CI, 1.33–4.37; p = 0.004). The overall survival was unaffected in either stratum. Conclusions: A high donor KIR B-content score protects against CMV reactivation in D−R+, but not D+R+, HSCT recipients, consistent with NK dominance when CMV-specific donor T-cells are sparse. A specific donor–recipient telomeric mismatch independently modifies the risk. Donor KIR profiling warrants prospective evaluation in donor-selection algorithms. Full article

(This article belongs to the Special Issue Natural Killer (NK) Cells in Immunity: Limitations and Potential)

► Show Figures

Graphical abstract

21 pages, 2975 KB

Open AccessArticle

Metformin Inhibits Cardiac Fibroblast Differentiation by Promoting Fatty Acid β-Oxidation: Implications for Age-Associated Cardiac Fibrosis

by Hridya Chempon, Sunita Kumari, Srinivasa Reddy Bonam and Srigiridhar Kotamraju

Cells 2026, 15(15), 1408; https://doi.org/10.3390/cells15151408 - 4 Aug 2026

Cited by 2 | Viewed by 661

Abstract

Cardiac fibrosis is a hallmark of pathological cardiac remodeling, characterized by fibroblast activation, excessive extracellular matrix deposition, and myocardial hypertrophy, ultimately leading to cardiac dysfunction. Aging exacerbates these processes through metabolic stress and impaired mitochondrial bioenergetics. Here, we investigated the anti-fibrotic effects of [...] Read more.

Cardiac fibrosis is a hallmark of pathological cardiac remodeling, characterized by fibroblast activation, excessive extracellular matrix deposition, and myocardial hypertrophy, ultimately leading to cardiac dysfunction. Aging exacerbates these processes through metabolic stress and impaired mitochondrial bioenergetics. Here, we investigated the anti-fibrotic effects of metformin and the role of fatty acid β-oxidation (FAO) in regulating cardiac fibroblast differentiation. Metformin significantly attenuated transforming growth factor-β (TGF-β)-induced cardiac fibroblast activation and the associated senescence-like phenotype. These effects were accompanied by enhanced FAO and increased mitochondrial oxygen consumption rate (OCR), indicating improved mitochondrial function. Importantly, inhibition of carnitine palmitoyltransferase-1 (CPT1) with etomoxir largely abolished the beneficial effects of metformin on mitochondrial respiration, fibroblast activation, and cellular senescence, demonstrating a critical role for FAO. Mechanistically, metformin increased CPT1 activity and acetyl-CoA levels while reducing malonyl-CoA accumulation, thereby promoting mitochondrial fatty acid utilization. These findings were corroborated in aged Apoe^−/− mice, where metformin reduced the expression of cardiac fibroblast differentiation markers and enhanced FAO-associated markers. Collectively, our findings demonstrate that metformin suppresses cardiac fibroblast differentiation and senescence by preserving mitochondrial bioenergetics through FAO-dependent mechanisms, revealing a metabolic basis for its anti-fibrotic actions and supporting its therapeutic potential in age-related cardiovascular disease. Full article

(This article belongs to the Special Issue Advances in the Cellular and Molecular Mechanisms of Cardiovascular Diseases)

► Show Figures

Graphical abstract

24 pages, 13296 KB

Open AccessArticle

Cblb Gene Editing in T Cells Sustains Expansion and Immunogenic CAR T Tumor Killing Under Chronic Antigenic Stimulation

by Daniel Schreiber, Sebastian Peer, Christina Lutz-Nicoladoni, Jiří Koutník, Viktor Lang, Viana Wille, Isabel Hölzl, Dominik Humer, Nino Tokic, Dorothee Freimark, Mario Kuttke, Alexander Dohnal, Romana Gugenberger, Thomas Gruber, Nikolaus Thuille, Dominik Wolf, Victoria Klepsch, Kerstin Siegmund and Gottfried Baier

Cells 2026, 15(15), 1407; https://doi.org/10.3390/cells15151407 - 3 Aug 2026

Viewed by 776

Abstract

CBL-B is an intracellular E3 ubiquitin ligase that acts as a T cell checkpoint by raising activation thresholds and limiting effector function. Here, genetic targeting of CBL-B enhances the performance of adoptively transferred T cells and CAR T cells under tumor microenvironment-like stress. [...] Read more.

CBL-B is an intracellular E3 ubiquitin ligase that acts as a T cell checkpoint by raising activation thresholds and limiting effector function. Here, genetic targeting of CBL-B enhances the performance of adoptively transferred T cells and CAR T cells under tumor microenvironment-like stress. In fully immunocompetent mouse models, Cblb deficiency or transient Cblb silencing improves control of MC-38 colon carcinoma and autochthonous mammary tumors, demonstrating that CBL-B restrains anti-tumor immunity. Cblb-deficient T cells show enhanced expansion and effector/effector-memory differentiation during an in vivo mixed lymphocyte reaction, confirming a cell-intrinsic brake function of CBL-B during sustained antigenic challenge. In a syngeneic Panc02-EpCAM model, Cblb-deficient anti-EpCAM CAR T cells show superior tumor control, enhanced infiltration, prolonged survival, and preserved effector function despite chronic antigen exposure and TGF-β. Mechanistically, Cblb targeting maintains granzyme B and IFN-γ production and is associated in vitro with increased GSDME-linked pyroptotic tumor cell death, consistent with features of immunogenic cell death. These findings extend previous CBL-B CAR T work from lymphocyte-deficient to immunocompetent settings and support CBL-B inhibition as a strategy to engineer CAR T cells that resist suppressive tumor microenvironments while promoting a more inflammatory mode of tumor killing. Full article

(This article belongs to the Special Issue Resistance of Hematological Malignancies and Solid Tumors to CAR T Cell Therapy)

► Show Figures

Figure 1

18 pages, 646 KB

Open AccessReview

Genetically Modified MSCs for Targeted Regeneration: Balancing Efficacy, Biosafety, and GMP Standardization

by Kristina V. Kitaeva, Ivan Y. Filin, Albert A. Rizvanov, Shahlo Turdikulova, Mirakbar Yakubov, Oksana Charishnikova and Valeriya V. Solovyeva

Cells 2026, 15(15), 1406; https://doi.org/10.3390/cells15151406 - 3 Aug 2026

Viewed by 466

Abstract

Mesenchymal stromal cells (MSCs) are a versatile platform for regenerative medicine and gene delivery because they combine multipotency, immunoregulatory activity, and injury-directed trafficking. Translation is nevertheless limited by donor- and tissue-dependent heterogeneity, variable biodistribution, and engineering-related risks. This review evaluates genetically modified MSCs [...] Read more.

Mesenchymal stromal cells (MSCs) are a versatile platform for regenerative medicine and gene delivery because they combine multipotency, immunoregulatory activity, and injury-directed trafficking. Translation is nevertheless limited by donor- and tissue-dependent heterogeneity, variable biodistribution, and engineering-related risks. This review evaluates genetically modified MSCs as medicinal products rather than as a general MSC class. We compare self-inactivating lentiviral (SIN-LV) transduction, which provides efficient and durable expression and has limited early clinical experience, with targeted genome editing, which can define the integration locus and copy number but remains constrained by variable precise knock-in efficiency, off-target and double-strand-break-associated effects, manufacturing cost, and the absence of long-term clinical safety data. We integrate preclinical and clinical evidence with GMP-compatible manufacturing, potency testing, genomic surveillance, and release criteria. Particular attention is given to safe-harbor integration and B2M/CIITA-based hypoimmunogenic designs as strategies to reduce engineering-related batch variability and HLA-dependent donor variability. Together, these developments support a transition from empirically optimized MSC preparations toward molecularly defined cellular medicines with predefined genotype, expression, potency, and safety attributes. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Cell Therapy, Regenerative Medicine, and Tissue Engineering)

► Show Figures

Figure 1

50 pages, 853 KB

Open AccessReview

Endometrial Vitamin D Signaling and Immune Escape in Recurrent Pregnancy Loss

by Charalampos Voros, Fotios Chatzinikolaou, Georgios Papadimas, Ioannis Papapanagiotou, Nektaria Zagorianakou, Ali Can Gunes, Aristotelis-Marios Koulakmanidis, Athanasios Karpouzos, Kyriakos Bananis, Charalampos Tsimpoukelis, Maria Anastasia Daskalaki, Christina-Maria Trakatelli, Stylianos Makrydimas, Nikolaos Thomakos, Panagiotis Antsaklis, Dimitrios Loutradis and George Daskalakis

Cells 2026, 15(15), 1405; https://doi.org/10.3390/cells15151405 - 3 Aug 2026

Viewed by 492

Abstract

Recurrent pregnancy loss (RPL) continues to be a significant challenge in reproductive medicine, particularly in women for whom standard examinations do not reveal a conclusive underlying reason. There is growing evidence that several instances may result from nuanced alterations in the endometrial milieu, [...] Read more.

Recurrent pregnancy loss (RPL) continues to be a significant challenge in reproductive medicine, particularly in women for whom standard examinations do not reveal a conclusive underlying reason. There is growing evidence that several instances may result from nuanced alterations in the endometrial milieu, particularly with decidualization and maternal–fetal immune tolerance. In recent years, vitamin D has gained recognition for its significance in early pregnancy, serving not only as a regulator of calcium metabolism but also as an active contributor to endometrial and immunological functions. The human endometrium exhibits the vitamin D receptor (VDR) and the enzyme CYP27B1, facilitating the local activation and signaling of vitamin D inside the uterine milieu. Experimental investigations have shown that vitamin D influences many processes critical for effective implantation and placentation, including stromal cell differentiation, cytokine equilibrium, trophoblast invasion, oxidative stress responses, and immune cell communication. Aberrant vitamin D signaling has been associated with heightened inflammatory activity, impaired decidual transformation, altered uterine natural killer cell functionality, and alteration of the Treg/Th17 equilibrium, all of which have been implicated in recurrent pregnancy loss. Concurrently, there is an increasing emphasis on the association between vitamin D and mitochondrial function as well as oxidative stress in decidual and endometrial cells. Interruption of these pathways may influence implantation and early embryonic development by impacting cellular metabolism and immunological control at the maternal–fetal interface. The clinical interest in vitamin D supplementation for women experiencing repeated reproductive failure is increasing; nevertheless, the existing results are conflicting, mostly due to the predominance of research focusing on circulating vitamin D levels rather than localized tissue-specific processes. Our review encapsulates new findings about the function of vitamin D in endometrial biology and reproductive immune regulation, emphasizing its involvement in decidualization, inflammatory signaling, oxidative stress, and maternal–fetal immunological tolerance in recurrent pregnancy loss. The potential ramifications for assisted reproduction and forthcoming tailored therapy techniques are also examined. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gynecological Disorders—Second Edition)

► Show Figures

Figure 1

17 pages, 7059 KB

Open AccessReview

Mitochondrial Dysfunction as a Driver of Meta-Inflammation in Aging: The Emerging Role of PDK4 in Bioenergetic Reprogramming and Inflammatory Amplification

by Md Riad Chowdhury, Gui-Hwa Jeong and In-Kyu Lee

Cells 2026, 15(15), 1404; https://doi.org/10.3390/cells15151404 - 3 Aug 2026

Viewed by 533

Abstract

Aging is accompanied by a progressive decline in mitochondrial quality, bioenergetic flexibility, and stress resilience. Aging mitochondria are increasingly recognized as active inflammatory signaling platforms rather than passive targets of cellular damage. Excess mtROS, leaked mtDNA, defective mitophagy, altered NAD⁺ metabolism, and [...] Read more.

Aging is accompanied by a progressive decline in mitochondrial quality, bioenergetic flexibility, and stress resilience. Aging mitochondria are increasingly recognized as active inflammatory signaling platforms rather than passive targets of cellular damage. Excess mtROS, leaked mtDNA, defective mitophagy, altered NAD⁺ metabolism, and impaired pyruvate oxidation together create a cellular environment that favors persistent inflammatory activation. These signals engage NF-κB, NLRP3 inflammasome, cGAS–STING, and SASP pathways, allowing mitochondrial stress to spread from organelle dysfunction to tissue-level inflammation. Within this framework, pyruvate dehydrogenase kinase 4 (PDK4) is of particular interest because it directly controls mitochondrial pyruvate entry through inhibition of the pyruvate dehydrogenase complex. By phosphorylating and inhibiting the pyruvate dehydrogenase complex, PDK4 limits mitochondrial pyruvate oxidation and favors lactate accumulation, fatty acid utilization, and redox-inflammatory signaling. Recent work in senescent cells links PDK4-dependent lactate accumulation to NOX1-derived ROS and SASP activity, suggesting a direct route by which altered fuel handling may reinforce inflammation. Here, we review mitochondrial dysfunction as the organizing principle of age-associated meta-inflammation, discuss PDK4 as a central metabolic checkpoint, examine tissue-specific consequences in muscle, adipose tissue, brain, and kidney, and evaluate therapeutic strategies aimed at restoring mitochondrial function to suppress chronic inflammation and preserve healthspan. Full article

► Show Figures

Figure 1

16 pages, 5886 KB

Open AccessArticle

Exploring Heteroplasmic Variants in mtDNA: Insights from Single-Cell Transcriptomics

by Marco Barresi, Ivano Di Meo, Alessia Nasca, Eleonora Lamantea, Andrea Legati and Daniele Ghezzi

Cells 2026, 15(15), 1403; https://doi.org/10.3390/cells15151403 - 3 Aug 2026

Viewed by 354

Abstract

Mitochondrial DNA (mtDNA) heteroplasmy, which is the coexistence of wild-type and mutant mtDNA variants within the same cell, plays a critical role in modulating cellular phenotypes, disease severity, and penetrance. Bulk RNA sequencing cannot detect cell-to-cell heteroplasmy variability, limiting our understanding of the [...] Read more.

Mitochondrial DNA (mtDNA) heteroplasmy, which is the coexistence of wild-type and mutant mtDNA variants within the same cell, plays a critical role in modulating cellular phenotypes, disease severity, and penetrance. Bulk RNA sequencing cannot detect cell-to-cell heteroplasmy variability, limiting our understanding of the pathological mechanisms of mtDNA variants. In this study, we leveraged single-cell RNA sequencing (scRNA-seq) combined with a robust bioinformatics pipeline to characterize mtDNA heteroplasmy. We employed four fibroblast lines from patients harboring heteroplasmic mtDNA pathogenic variants in genes encoding respiratory complex I subunits. While RNA heteroplasmy corresponded to DNA-based measurements at the bulk level, single-cell analysis uncovered a diverged distribution in three out of four lines: most cells had near-homoplasmic (wild-type or mutant) mtDNA, with few cells showing intermediate levels. Furthermore, we found that high mutation levels correlate with transcriptional profile changes, although these responses were highly sample-specific, suggesting that the nuclear background and cellular context critically influence mitochondrial dysfunction and compensatory mechanisms. Our findings highlight the potential of single-cell technologies to better understand the complex link between mtDNA genetic diversity and mitochondrial phenotypic variability and to study crucial aspects of mitochondrial biology and pathology, such as clonal dynamics, at single-cell resolution. Full article

(This article belongs to the Section Mitochondria)

► Show Figures

Figure 1

27 pages, 10347 KB

Open AccessArticle

JAK and MEK Pathway Regulation of Mitochondrial Activity as Possible Targets for Saphenous Vein Smooth Muscle Cell Dysfunction in Diabetes

by Israel O. Bolanle, Florah T. Moshapa, Gillian A. Durham, James P. Hobkirk, Kirsten Riches-Suman, Mahmoud Loubani, Roger G. Sturmey and Timothy M. Palmer

Cells 2026, 15(15), 1402; https://doi.org/10.3390/cells15151402 - 3 Aug 2026

Cited by 1 | Viewed by 448

Abstract

While glucose-driven mitochondrial dysfunction has been proposed to promote vascular dysfunction responsible for saphenous vein graft failure (VGF) following bypass surgery, the impact of type 2 diabetes mellitus (T2DM) on mitochondrial function in human saphenous vein smooth muscle cells (HSVSMCs) responsible for maladaptive [...] Read more.

While glucose-driven mitochondrial dysfunction has been proposed to promote vascular dysfunction responsible for saphenous vein graft failure (VGF) following bypass surgery, the impact of type 2 diabetes mellitus (T2DM) on mitochondrial function in human saphenous vein smooth muscle cells (HSVSMCs) responsible for maladaptive remodelling is unknown. Our aim was to identify signalling pathways that mediate any mitochondrial dysfunction in HSVSMCs in vitro and assess the impact of T2DM. HSVSMCs explanted from surplus HSV tissues from consenting T2DM and non-diabetic patients undergoing coronary artery bypass graft surgery were treated with known activators and inhibitors of the JAK/STAT and MAPK/ERK pathways. Following this, real-time oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) measures of mitochondrial function were then determined. Our findings revealed that both IL-6/sIL-6Rα trans-signalling complexes and platelet-derived growth factor-BB (PDGF-BB) significantly increased OCR in HSVSMCs from T2DM patients but not non-diabetic controls. Meanwhile, only PDGF-BB increased ECAR in HSVSMCs from T2DM patients but not in non-diabetic controls. The observed increases in OCR and ECAR were abolished by JAK1/2-selective inhibitor ruxolitinib. Furthermore, thrombin caused a significant increase in OCR, specifically in HSVSMCs from T2DM patients, and this effect was abolished by the MEK1/2-selective inhibitor trametinib. Both ruxolitinib and trametinib significantly reduced basal OCR and ECAR in HSVSMCs from both T2DM and non-diabetic patients. Together, these findings demonstrate a JAK/STAT- and MAPK/ERK-mediated regulation of mitochondrial function in HSVSMCs. As such, they represent potential targets for regulation of HSVSMC function that can be explored for drug development to limit saphenous VGF in T2DM. Full article

(This article belongs to the Special Issue Advances in the Cellular and Molecular Mechanisms of Cardiovascular Diseases)

► Show Figures

Figure 1

17 pages, 3444 KB

Open AccessArticle

GLUD1 Inhibition Disrupts Glutamate Homeostasis and Induces Metabolic and Redox Stress in Gliomas

by Malgorzata Trybula, Małgorzata Łysiak, Emilia Wiechec, Annika Malmström and Peter Söderkvist

Cells 2026, 15(15), 1401; https://doi.org/10.3390/cells15151401 - 3 Aug 2026

Viewed by 543

Abstract

Glutamate dehydrogenase (GLUD1) links glutamine metabolism and redox regulation, yet its prognostic and functional relevance across different glioma subtypes warrants further study. Here, we show that GLUD1 expression was inversely associated with tumor grade and positively associated with survival across glioma subtypes, a [...] Read more.

Glutamate dehydrogenase (GLUD1) links glutamine metabolism and redox regulation, yet its prognostic and functional relevance across different glioma subtypes warrants further study. Here, we show that GLUD1 expression was inversely associated with tumor grade and positively associated with survival across glioma subtypes, a relationship not fully recapitulated by broader glutaminolysis-related gene signatures. To investigate the consequences of GLUD1 inhibition, we treated endogenous IDH-mutant and IDH-wildtype glioma cell lines with the reported GLUD1 inhibitor R162. GLUD1 inhibition reduced viability in all cell lines tested. This effect was not rescued by α-ketoglutarate (α-KG) supplementation, indicating that impaired tricarboxylic acid (TCA) cycle anaplerosis was not the primary mechanism underlying GLUD1 dependency. Instead, GLUD1 inhibition caused intracellular glutamate accumulation, increased reactive oxygen species (ROS), γ-H2AX induction, and elevated intracellular calcium, while complementary in silico analyses predicted disruption of mitochondrial membrane potential following R162 exposure. Together, these findings indicate that GLUD1 inhibition induces metabolic and redox stress associated with disrupted glutamate and calcium homeostasis and DNA damage. Our findings distinguish the favorable prognostic value of GLUD1 expression from the cellular vulnerability revealed by its inhibition, supporting further investigations of GLUD1 as both a prognostic biomarker and potential therapeutic target in glioma. Full article

► Show Figures

Figure 1

24 pages, 2369 KB

Open AccessReview

bHLH Family Transcription Factors: Molecular Switches in Plant Specialized Metabolism

by Xinpei Han, Guodong Chen, Jun Peng, Nan Cao, Fuguang Li and Sumei Wan

Cells 2026, 15(15), 1400; https://doi.org/10.3390/cells15151400 - 3 Aug 2026

Viewed by 630

Abstract

Plant specialized metabolites connect genetic programs and environmental responses with ecologically and economically valuable natural products. Their accumulation is rarely constitutive, varying instead with tissue identity, developmental stage, stress exposure, hormone signaling, and cellular storage capacity. This review examines basic helix-loop-helix (bHLH) transcription [...] Read more.

Plant specialized metabolites connect genetic programs and environmental responses with ecologically and economically valuable natural products. Their accumulation is rarely constitutive, varying instead with tissue identity, developmental stage, stress exposure, hormone signaling, and cellular storage capacity. This review examines basic helix-loop-helix (bHLH) transcription factors as regulatory switch points in plant specialized metabolism, with emphasis on the jasmonate-JAZ-MYC module. In resting tissues, JAZ repressors constrain MYC/bHLH activity; after wounding, herbivory, pathogen challenge, or elicitation, jasmonoyl-isoleucine triggers COI1-dependent JAZ turnover, releasing MYC factors to bind E-box/G-box motifs, recruit coregulators such as MED25, and activate biosynthetic genes or downstream transcription-factor cascades. Plant lineages have repeatedly adapted this regulatory logic to control terpenoids, alkaloids, phenylpropanoids, flavonoids, glucosinolates, phytoalexins, and related metabolites. Comparative examples include Arabidopsis sesquiterpenes and glucosinolates, Taxus taxanes, Artemisia artemisinin, Catharanthus terpenoid indole alkaloids, Salvia phenolic acids and tanshinones, Ginkgo terpene trilactones, rice diterpenoid phytoalexins, and cotton gossypol. Across these systems, bHLH output depends on dimer choice, promoter grammar, chromatin accessibility, hormone crosstalk, partner transcription factors, and cell-type competence. Six shared principles emerge: signal gating, topology matched to pathway architecture, partner-dependent promoter decoding, spatial competence, feedback rheostats, and evidence-dependent transferability. We further discuss evidence standards, multi-omics-guided factor discovery, miRNA-mediated post-transcriptional control, and engineering strategies for crop defense, food quality, medicinal-metabolite production, and synthetic biology. Unlike pathway- or MYC2-centered surveys, this review organizes the literature within a direct–cascade–hybrid framework that integrates promoter grammar, spatial competence, storage anatomy, and an explicit evidence hierarchy. Full article

(This article belongs to the Special Issue New Insights into Plant Bioactive Compounds)

► Show Figures

Figure 1

27 pages, 3608 KB

Open AccessReview

Targeting DOT1L Epigenetic Moonlighting in MLL-Rearranged Leukemia

by Dikshat Gopal Gupta, Monika Gupta, Ahmad Hasan Othman, Uzer Abdulaziz Memon, Gary E. Schiltz and Sarki A. Abdulkadir

Cells 2026, 15(15), 1399; https://doi.org/10.3390/cells15151399 - 3 Aug 2026

Viewed by 865

Abstract

KMT2A-rearranged (MLL-r) leukemias are highly aggressive hematological malignancies that require improved targeted therapies. DOT1L (histone H3K79 methyltransferase) functions as a critical oncogenic driver and represents an important therapeutic target in these high-risk leukemias. However, clinical responses to the first-in-class DOT1L inhibitor pinometostat (EPZ5676) [...] Read more.

KMT2A-rearranged (MLL-r) leukemias are highly aggressive hematological malignancies that require improved targeted therapies. DOT1L (histone H3K79 methyltransferase) functions as a critical oncogenic driver and represents an important therapeutic target in these high-risk leukemias. However, clinical responses to the first-in-class DOT1L inhibitor pinometostat (EPZ5676) have been modest, attributed to suboptimal pharmacokinetics and, more fundamentally, to the recognition that DOT1L possesses methyltransferase-independent functions that evade catalytic inhibition. This highlights the need for strategies that abrogate the full spectrum of DOT1L activity to effectively treat these high-risk leukemias. Proteolysis-targeting chimeras (PROTACs), which induce selective degradation of the DOT1L protein rather than inhibiting its catalytic activity, have therefore emerged as a promising approach. Notably, VHL-recruiting DOT1L PROTACs, such as DOT1L808, have demonstrated improved pharmacokinetic profiles and potent antileukemic activity in preclinical in vivo models. However, these findings remain preclinical, and significant challenges including oral bioavailability, potential toxicity, and lack of clinical validation must be addressed before clinical translation. In this review, we provide an overview of the evolving understanding of the biology of DOT1L, discuss existing MLL small molecule therapies, and evaluate current advances in therapeutically targeting DOT1L, with particular focus on the targeted degradation of DOT1L as a promising therapeutic strategy for high-risk KMT2A-r leukemia. Full article

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Cells, Volume 15, Issue 15 (August-1 2026) – 114 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI