Cells

16 pages, 2164 KB

Open AccessArticle

Recombinant Human Decorin Normalizes the Active Features of Breast Cancer-Associated Fibroblasts

by Wafaa A. Aljagthmi, Ayodele A. Alaiya, Maha Daghestani, Falah H. Al-Mohanna and Abdelilah Aboussekhra

Cells 2026, 15(3), 311; https://doi.org/10.3390/cells15030311 - 6 Feb 2026

Abstract

Cancer-associated fibroblasts (CAFs), the major constituent of the tumor microenvironment, are considered the most active cells and key contributors to tumor resistance, recurrence, and metastasis. Therefore, we have investigated here the potential normalization of the active features of breast CAFs with decorin (DCN), [...] Read more.

Cancer-associated fibroblasts (CAFs), the major constituent of the tumor microenvironment, are considered the most active cells and key contributors to tumor resistance, recurrence, and metastasis. Therefore, we have investigated here the potential normalization of the active features of breast CAFs with decorin (DCN), a small leucine-rich proteoglycan that acts as an oncogene suppressor. We have first shown that rhDCN modulates the expression of a plethora of proteins involved in different signaling pathways, including STAT3/NF-κB and ERK. Consequently, rhDCN repressed the important active CAF biomarkers α-SMA, IL-6, and SDF-1 through inhibition of the STAT3/AUF-1 pathway, in cells grown as 2D and 3D cultures. Furthermore, rhDCN had a strong downregulation effect on FAP-α, a key biomarker of active CAFs, and suppressed their proliferative and invasive capacities through upregulation of p16 and p21, and downregulation of MMP-2 and MMP-9. Furthermore, rhDCN suppressed the paracrine effects of active CAFs in promoting epithelial-to-mesenchymal transition (EMT) and cancer stem cells in breast cancer cells, both in vitro and in orthotopic tumor xenografts. Importantly, rhDCN-related normalization of active CAFs features was persistent through cellular passaging, and was not accompanied by cytotoxicity. Together, these findings have revealed rhDCN as a promising anti-breast cancer therapeutic cytokine through suppression of the non-cell-autonomous cancer-promoting effects of active CAFs. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Challenges and Directions)

19 pages, 2730 KB

Open AccessArticle

Metformin Suppresses Glioblastoma Tumor Growth and Progression Through the AMPK/FoxO3a/Survivin Axis

by Fabiola Cavaliere, Michele Pellegrino, Alessandro Cormace, Sofia Spadafora, Mariarosa Fava, Seung Ho Yang, Jung Eun Lee, Marta Claudia Nocito, Rosa Sirianni, Ivan Casaburi, Cecilia Garofalo, Diego Sisci, Catia Morelli and Marilena Lanzino

Cells 2026, 15(3), 310; https://doi.org/10.3390/cells15030310 - 6 Feb 2026

Abstract

Glioblastoma (GB) is one of the most aggressive malignant brain tumors. Due to the high invasiveness of this cancer, surgical removal is often not possible, and relapses after surgery are very common, making current treatments ineffective. Developing new therapies or treatment combinations remains [...] Read more.

Glioblastoma (GB) is one of the most aggressive malignant brain tumors. Due to the high invasiveness of this cancer, surgical removal is often not possible, and relapses after surgery are very common, making current treatments ineffective. Developing new therapies or treatment combinations remains a major challenge in managing GB. Metformin (MET), an anti-diabetic medication, has recently gained attention for its potential anticancer effects. To better understand how MET inhibits GB growth at the molecular level, we studied its impact on survivin, a member of the inhibitor of apoptosis (IAP) family that is essential for GB cell survival, resistance to radio- and chemotherapy, and tumor recurrence. Using T98G and U87-MG cell lines, we performed cell viability, migration, and invasion assays, along with Western blot analysis, ChIP assays, and gene silencing experiments to examine key signaling pathways. We found that MET effectively inhibits the growth, viability, and invasiveness of GB cell lines through a molecular mechanism involving activation of the AMPK/FoxO3a/survivin pathway. In vivo studies support these findings, showing increased FoxO3a and decreased survivin in brain tissue sections from metformin-treated mice compared with untreated controls. These results suggest new possibilities for repurposing MET as an adjuvant treatment for GB. Full article

(This article belongs to the Topic Advances in Glioblastoma: From Biology to Therapeutics)

29 pages, 798 KB

Open AccessReview

Decoding Glioblastoma Through Liquid Biopsy: Molecular Insights and Clinical Prospects

by Tomasz Wasiak, Maria Jaskólska, Kamil Filiks, Jakub Bartkowiak and Adrianna Rutkowska

Cells 2026, 15(3), 309; https://doi.org/10.3390/cells15030309 - 6 Feb 2026

Abstract

Liquid biopsy (LB) offers a minimally invasive approach to characterizing and monitoring glioblastoma (GB), a tumor marked by extensive heterogeneity, limited surgical accessibility and rapid molecular evolution. By analyzing circulating tumor-derived components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), circulating RNA [...] Read more.

Liquid biopsy (LB) offers a minimally invasive approach to characterizing and monitoring glioblastoma (GB), a tumor marked by extensive heterogeneity, limited surgical accessibility and rapid molecular evolution. By analyzing circulating tumor-derived components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), circulating RNA species and circulating tumor cells (CTC), LB provides dynamic molecular information that cannot be captured by neuroimaging or single-site tissue sampling. Cerebrospinal fluid (CSF) currently yields the highest sensitivity for detecting tumor-specific alterations, while plasma enables repeat monitoring despite lower biomarker abundance. EVs have gained particular prominence due to their ability to preserve DNA, RNA, and protein cargo that reflects key genomic changes, treatment resistance mechanisms, and immune evasion. Although advances are substantial, clinical implementation remains constrained by low analyte concentrations, methodological variability, limited standardization and the high cost of testing, which is rarely reimbursed by insurers. This review summarizes current evidence on circulating biomarkers in GB and highlights research priorities essential for integrating LB into future diagnostic and therapeutic workflows. Full article

(This article belongs to the Special Issue Gliomas: Molecular Insights, Next-Generation Therapies, and Precision Targeting)

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19 pages, 3462 KB

Open AccessArticle

Fatty Acid Composition, at Equivalent Lipid Exposure, Dictates Human Macrophage Polarization via PPARγ Signaling

by Halemah AlSaeed, Hesah Almusallam, Shayndel Menezes, Hessah Almelaifi, Hussah Alonaizi, Mohammad Almejaimi, Rasheed Ahmad and Fatema Al-Rashed

Cells 2026, 15(3), 308; https://doi.org/10.3390/cells15030308 - 6 Feb 2026

Abstract

Dietary fats are consumed as mixtures, yet it remains unclear whether fatty acid composition, independent of fat content, dictates human macrophage polarization. We compared two defined mixtures containing identical fatty acids (palmitic, oleic, and linoleic acids) in different ratios: a palmitate-enriched mixture (4:3:3) [...] Read more.

Dietary fats are consumed as mixtures, yet it remains unclear whether fatty acid composition, independent of fat content, dictates human macrophage polarization. We compared two defined mixtures containing identical fatty acids (palmitic, oleic, and linoleic acids) in different ratios: a palmitate-enriched mixture (4:3:3) and an unsaturated fat-dominant mixture (2:4:4). In primary human monocyte-derived macrophages, palmitate enrichment increased CD14+CD11b+HLA-DR+ pro-inflammatory polarization, whereas the unsaturated fat-dominant mixture increased CD14+CD11b+CD163+ anti-inflammatory polarization. Mechanistic studies in THP-1-derived macrophages recapitulated these phenotype shifts and identified a reciprocal nuclear-receptor program: palmitate enrichment induced peroxisome proliferator-activated receptor gamma (PPARγ), together with ER-stress mediators EIF2AK3 and DDIT3, while the unsaturated fat-dominant mixture preferentially induced PPARα and IRF4. Pharmacologic modulation demonstrated functional dependence on PPARγ: GW9662 attenuated palmitate-driven M1-like polarization, whereas rosiglitazone disrupted the protective program under unsaturated fat-dominant conditions. These findings show that fatty acid composition, at equivalent total lipid concentration, is a dominant determinant of human macrophage inflammatory fate and highlight PPARγ as a context-dependent lipid sensor. Full article

(This article belongs to the Collection Research Advances in Cellular Metabolism)

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35 pages, 1420 KB

Open AccessReview

Skeletal Involvement in Systemic Mastocytosis: Pathophysiology, Clinical Management, Standards of Care, and Novel Therapeutic Strategies

by Manlio Fazio, Adele Bottaro, Maria Elisa Nasso, Fabio Stagno and Alessandro Allegra

Cells 2026, 15(3), 307; https://doi.org/10.3390/cells15030307 - 6 Feb 2026

Abstract

Systemic mastocytosis comprises a group of clonal mast cell disorders characterized by multisystem involvement. Bone involvement represents a major source of morbidity, particularly in young men affected by indolent systemic mastocytosis. This review provides an integrated and up-to-date overview of SM-related bone disease. [...] Read more.

Systemic mastocytosis comprises a group of clonal mast cell disorders characterized by multisystem involvement. Bone involvement represents a major source of morbidity, particularly in young men affected by indolent systemic mastocytosis. This review provides an integrated and up-to-date overview of SM-related bone disease. We dissect the dual and context-dependent role of mast cells in bone remodeling, detailing how they promote osteoclastogenesis, suppress osteoblast function, and, in advanced disease, drive osteosclerosis. We critically appraise available treatments, including classic anti-resorptive therapy and emerging anabolic strategies. We further discuss the transformative impact of KIT-directed tyrosine kinase inhibitors, particularly avapritinib, which has demonstrated for the first time the ability to reverse not only osteoporosis but also osteosclerosis. Finally, we explore the emerging role of machine learning models in SM, proposing their application to individualized prediction of osteoporosis and fracture risk in SM. By bridging clinical care, bone biology, and therapeutic advances, this review underscores the need for a paradigm shift in which SM-related bone disease is recognized as a dynamic process requiring early identification, integrated risk stratification, and coordinated use of anti-resorptive, disease-modifying, and data-driven precision approaches to prevent fractures and improve long-term outcomes and quality of life in this delicate category of patients. Full article

(This article belongs to the Special Issue Mast Cells in Health and Disease: Current Insights and Future Perspectives on Development, Activation, Functional Roles, and Therapeutic Strategies)

14 pages, 2355 KB

Open AccessArticle

Tracking Focal Adhesion Turnover: A Novel Reporter for FA-Phagy Flux

by Kuizhi Qu, Mengjun Dai, Ying Jiang, Sophie Liu, John P. Hagan, Louise D. McCullough, Zhen Xu and Yan-Ning Rui

Cells 2026, 15(3), 306; https://doi.org/10.3390/cells15030306 - 6 Feb 2026

Abstract

Focal adhesions (FAs) are critical multi-protein complexes regulating cell adhesion, migration, and survival, and their dysregulation contributes to cancer metastasis and vascular diseases. Despite extensive research on FA formation, little is known about FA turnover, particularly its regulation by autophagy. This study introduces [...] Read more.

Focal adhesions (FAs) are critical multi-protein complexes regulating cell adhesion, migration, and survival, and their dysregulation contributes to cancer metastasis and vascular diseases. Despite extensive research on FA formation, little is known about FA turnover, particularly its regulation by autophagy. This study introduces a novel tandem fluorescence reporter capable of tracking the entire FA-phagy flux, from autophagosome formation to lysosomal degradation. The reporter, based on a red–green fluorescence system with a lysosome-specific cleavage site, integrates seamlessly into endogenous focal adhesion complexes, demonstrating sensitivity and specificity to autophagy stimuli. Validated in multiple cell lines, the tool revealed dynamic FA-phagy responses to starvation-induced autophagy and the involvement of autophagy regulators such as mTOR and ATG genes. This versatile reporter provides a powerful tool for investigating FA-phagy mechanisms, with significant implications for cancer biology and vascular research. Full article

(This article belongs to the Special Issue Cancer Cell Signaling, Autophagy and Tumorigenesis)

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17 pages, 1105 KB

Open AccessArticle

Functional Roles of Src Kinase Activity in Oocyte Maturation and Artificial Egg Activation in Xenopus laevis

by Ken-ichi Sato and Alexander A. Tokmakov

Cells 2026, 15(3), 305; https://doi.org/10.3390/cells15030305 - 6 Feb 2026

Abstract

Src family tyrosine kinases regulate oocyte maturation and fertilization in many species, yet their physiological roles in Xenopus laevis (X. laevis) remain incompletely defined. Here, we generated three X. laevis Src (xSrc) constructs with defined point mutations allowing for selective immunochemical [...] Read more.

Src family tyrosine kinases regulate oocyte maturation and fertilization in many species, yet their physiological roles in Xenopus laevis (X. laevis) remain incompletely defined. Here, we generated three X. laevis Src (xSrc) constructs with defined point mutations allowing for selective immunochemical detection and controlled modulation of kinase activity: wild type (xSrcWT, Arg121His), constitutively active (xSrcKA, Arg121His/Tyr526Phe), and kinase-negative (xSrcKN, Arg121His/Lys294Met). Capped mRNAs were microinjected into immature oocytes, and effects on meiotic maturation and egg activation were analyzed. All constructs produced detectable Src protein within 4–5 h after injection without inducing progesterone-independent maturation. Following progesterone treatment, MAP kinase phosphorylation, CDK1 activation, and germinal vesicle breakdown (GVBD) occurred normally in all groups, although xSrcKA-expressing oocytes showed a modest but reproducible acceleration of MAPK activation and GVBD. Global tyrosine phosphorylation analysis revealed increased phosphorylation of several proteins, including a prominent ~50 kDa substrate, specifically in xSrcKA oocytes. After maturation, oocytes were subjected to artificial activation. xSrcKN-expressing oocytes responded normally to Ca²⁺ ionophore (A23187), indicating that Src activity is not required for direct Ca²⁺-mediated activation. In contrast, xSrcKN oocytes exhibited markedly reduced activation in response to hydrogen peroxide or Cathepsin B, which stimulate membrane-associated signaling pathways. These findings demonstrate that Src kinase activity is required for membrane signal-mediated egg activation but is dispensable for activation driven by direct intracellular Ca²⁺ elevation. Collectively, our results identify Src kinase as a positive regulator of progesterone-induced meiotic maturation and a critical mediator of specific fertilization-like activation pathways in X. laevis. Full article

(This article belongs to the Section Reproductive Cells and Development)

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28 pages, 1384 KB

Open AccessReview

Artificial Intelligence for Exosomal Biomarker Discovery for Cardiovascular Diseases: Multi-omics Integration, Reproducibility, and Translational Prospects

by Rasit Dinc and Nurittin Ardic

Cells 2026, 15(3), 304; https://doi.org/10.3390/cells15030304 - 5 Feb 2026

Abstract

Exosomes and other extracellular vesicles (EVs) carry microRNAs, proteins, and lipids that reflect cardiovascular pathophysiology and can enable minimally invasive biomarker discovery. However, EV datasets are highly dimensional and heterogeneous, strongly influenced by pre-analytic variables and non-standardized isolation/characterization workflows, limiting reproducibility across studies. [...] Read more.

Exosomes and other extracellular vesicles (EVs) carry microRNAs, proteins, and lipids that reflect cardiovascular pathophysiology and can enable minimally invasive biomarker discovery. However, EV datasets are highly dimensional and heterogeneous, strongly influenced by pre-analytic variables and non-standardized isolation/characterization workflows, limiting reproducibility across studies. Artificial intelligence (AI), including machine learning (ML), deep learning (DL), and network-based approaches, can support EV biomarker development by integrating multi-omics profiles with clinical metadata. These approaches enable feature selection, disease subtyping, and interpretable model development. Among the AI approaches evaluated, ensemble methods (Random Forest, gradient boosting) demonstrate the most consistent performance for EV biomarker classification (AUC 0.80–0.92), while graph neural networks (GNNs) are particularly promising for path integration but require larger validation cohorts. Evolutionary neural networks applied to EV morphological features yield comparable discrimination but face interpretability challenges for clinical use. Current studies report promising discrimination performance for selected EV-derived panels in acute myocardial infarction and heart failure. However, most evidence remains exploratory, based on small cohorts (n < 50) and limited external validation. For clinical implementation, EV biomarkers need direct comparison against established standards (high-sensitivity troponin and natriuretic peptides), supported by locked-in assay plans, and validation in multicenter cohorts using MISEV-aligned protocols and transparent AI reporting practices. Through a comprehensive, integrative, and comparative analysis of AI methodologies for EV biomarker discovery, together with explicit criteria for reproducibility and translational readiness, this review establishes a practical framework to advance exosomal diagnostics from exploratory research toward clinical implementation. Full article

21 pages, 2427 KB

Open AccessArticle

PCIF1 Attenuates Type I Interferon Induction by Inhibiting IRF3 Activation in a Methyltransferase-Independent Manner

by Ryoya Kano, Chihiro Oyama, Chihiro Ikeda, Akiko Inujima, Keiichi Koizumi, Shinichiro Akichika, Tsutomu Suzuki, Aki Tanaka, Yoshiaki Ohkuma and Yutaka Hirose

Cells 2026, 15(3), 303; https://doi.org/10.3390/cells15030303 - 5 Feb 2026

Abstract

PCIF1 is primarily recognized as an RNA methyltransferase that mediates N⁶-methylation of cap-proximal adenosine (m⁶Am) and plays diverse roles in gene expression. In this study, we uncover a novel role for PCIF1 as a crucial negative regulator of type [...] Read more.

PCIF1 is primarily recognized as an RNA methyltransferase that mediates N⁶-methylation of cap-proximal adenosine (m⁶Am) and plays diverse roles in gene expression. In this study, we uncover a novel role for PCIF1 as a crucial negative regulator of type I interferon (IFN) induction, a pathway critical for antiviral immunity whose dysregulation leads to inflammatory and autoimmune diseases. We demonstrate that PCIF1 deficiency robustly enhances the poly(I:C)-induced type I IFN response, accompanied by augmented STAT1 activation and interferon-stimulated gene (ISG) expression. Mechanistically, PCIF1 suppresses IFNB1 transcription by attenuating IRF3 phosphorylation and nuclear translocation, as shown by increased nascent IFNB1 mRNA synthesis and promoter activity in PCIF1-deficient cells, without affecting the mRNA stability. Crucially, this suppressive function was independent of PCIF1’s canonical RNA methyltransferase activity, as both wild-type PCIF1 and a methyltransferase-inactive mutant effectively attenuated type I IFN induction. Collectively, our findings establish PCIF1 as a novel methyltransferase-independent suppressor of type I IFN responses, revealing its previously unrecognized non-catalytic function. This discovery offers critical insights into the multifaceted regulation of innate immunity and highlights PCIF1’s non-catalytic function as a promising therapeutic target for modulating antiviral responses and inflammatory diseases. Full article

(This article belongs to the Special Issue From Signals to Shape: Molecular Control of Cellular Plasticity Through Epigenetic, Transcriptomic, and Immune Mechanisms)

33 pages, 5788 KB

Open AccessArticle

Temperature-Dependent and Semi-Quantitative Enzyme Profiles of Malacosoma disstria (Lepidoptera: Lasiocampidae) Hemocytic Cell Lines

by Paschalis Giannoulis and Helen Kalorizou

Cells 2026, 15(3), 302; https://doi.org/10.3390/cells15030302 - 5 Feb 2026

Abstract

Insect hemocytic cell lines offer substantial advantages over primary, in vivo hemocyte cultures, fundamentally transforming experimental approaches in cellular immunology and related fields. Selected Malacosoma disstria cell lines were characterized for optimal growth temperatures, morphogenesis, blebbing, extracellular enzyme profiles, and their interactions with [...] Read more.

Insect hemocytic cell lines offer substantial advantages over primary, in vivo hemocyte cultures, fundamentally transforming experimental approaches in cellular immunology and related fields. Selected Malacosoma disstria cell lines were characterized for optimal growth temperatures, morphogenesis, blebbing, extracellular enzyme profiles, and their interactions with material (polystyrene) and microbial (Bacillus subtilis) surfaces. The adhesive hemocyte lines UA-Md221 and Md108 showed optimal growth at 28 °C, whereas UA-Md203 and Md66 grew best at 21 °C, with Md66 tolerating 21–28 °C. Md108 demonstrated a broader temperature tolerance than other adherent cultures. Both Md108 and UA-Md221 adhered to polystyrene within 24 h post-subculturing, although protease-induced morphological changes in modified Grace’s medium continued through 48 h and 72 h, respectively. Culture quality was monitored by assessing the release of multiple enzymes, including alkaline and acid phosphatases, esterases and lipases, aminopeptidases, proteases, glycosidases, and hydrolases from the cell lines at 50% confluency in modified Grace’s medium. Fetal bovine serum showed elevated esterase lipase (C8) and phosphoamidase activities when diluted in Grace’s medium and phosphate buffered saline (PBS). Exposure to dead B. subtilis suspended in PBS induced quantitative and qualitative alterations in the enzyme secretion profiles of Md66 and Md108 cultures. We conclude that semi-quantitative assessments of hemocytic cell lines can provide valuable insights for the time window of each enzyme release, revealing immune and metabolic signaling patterns. Full article

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26 pages, 15250 KB

Open AccessFeature PaperArticle

Integrative Machine Learning and Experimental Validation Identify FIS1 as a Candidate Biomarker Linked to Mitochondrial Dynamics in Pulmonary Hypertension

by Yu Zhang, Qing Dai, Lijun Gong, Runxiu Zheng, Wei Huang, Feiying Wang, Rong Yuan, Lan Song and Aiguo Dai

Cells 2026, 15(3), 301; https://doi.org/10.3390/cells15030301 - 5 Feb 2026

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Abstract

Pulmonary hypertension (PH) is characterized by progressive pulmonary vascular remodeling and a paucity of effective therapeutic interventions. Although dysregulated mitochondrial dynamics are implicated in this remodeling process, the key regulatory molecules and downstream mechanisms remain incompletely defined. This study aimed to systematically characterize [...] Read more.

Pulmonary hypertension (PH) is characterized by progressive pulmonary vascular remodeling and a paucity of effective therapeutic interventions. Although dysregulated mitochondrial dynamics are implicated in this remodeling process, the key regulatory molecules and downstream mechanisms remain incompletely defined. This study aimed to systematically characterize molecular alterations associated with mitochondrial dynamics in PH and to explore the functional relevance and potential mechanisms of prioritized candidate genes. We integrated transcriptomic datasets from PH models with MitoCarta annotations to identify mitochondria-related differentially expressed genes. Candidate genes were prioritized using WGCNA and three machine-learning algorithms (LASSO, SVM-RFE, and random forest). These candidates were then experimentally evaluated in a hypoxia-induced PH mouse model and hypoxia-stimulated mouse pulmonary artery smooth muscle cells (mPASMCs) using qRT–PCR, Western blotting, immunohistochemistry, and transmission electron microscopy. Functional assays and assessments of mitochondrial injury were performed to investigate pathogenic relevance. Our analysis identified four key genes, with FIS1 showing high ROC/AUC-based discriminatory performance in both the training dataset and the independent replication dataset. Hypoxia was associated with increased FIS1 expression, mitochondrial fragmentation, loss of mitochondrial membrane potential, and ROS accumulation. We further observed that FIS1 knockdown suppressed mPASMC proliferation and migration, alleviated mitochondrial injury, and attenuated ferroptosis-associated alterations, accompanied by reduced lipid peroxidation, decreased Fe²⁺ accumulation, and partial normalization of ferroptosis-related marker proteins. Taken together, these findings suggest that FIS1 may contribute to PH pathogenesis through mitochondrial fission and ferroptosis-associated stress, potentially promoting aberrant PASMC phenotypes and pulmonary vascular remodeling. This work provides a mechanistic rationale and molecular leads that may inform molecular stratification and mechanistically informed therapeutic exploration targeting mitochondrial pathways in PH. Full article

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

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34 pages, 2379 KB

Open AccessArticle

Form Meets Function: Fiber Architecture Directs Proliferation and Differentiation in Gingival Keratinocytes

by Imke Ramminger, Thorsten Steinberg, Bernd Rolauffs, Mischa Selig and Pascal Tomakidi

Cells 2026, 15(3), 300; https://doi.org/10.3390/cells15030300 - 5 Feb 2026

Abstract

Precise control of keratinocyte proliferation and differentiation is critical for oral epithelial regeneration, yet the mechanobiological cues guiding these processes remain incompletely defined. Here, we systematically evaluated how electrospun polycaprolactone (PCL) scaffolds with defined fiber orientations (aligned vs. random) and diameters (600–800 nm, [...] Read more.

Precise control of keratinocyte proliferation and differentiation is critical for oral epithelial regeneration, yet the mechanobiological cues guiding these processes remain incompletely defined. Here, we systematically evaluated how electrospun polycaprolactone (PCL) scaffolds with defined fiber orientations (aligned vs. random) and diameters (600–800 nm, 1.2–1.7 µm, 2.0–2.5 µm) direct gingival keratinocyte fate. Using immortalized human gingival keratinocytes, we assessed cell and nuclear morphology, proliferation dynamics, differentiation marker expression, and the effects of basal keratin (KRT5/KRT14) knockdown. Quantitative morphological analysis revealed scaffold-dependent changes in cell shape: aligned medium-diameter fibers (with fiber diameters of 1.2–1.7 µm) induced pronounced cell and nuclear elongation, whereas random fibers (600–800 nm) promoted larger, more rounded cell and nuclear shapes. Time-resolved EdU assays indicated that aligned scaffolds supported sustained proliferation, whereas random scaffolds elicited a transient proliferative burst followed by a decline. Gene expression analysis (ddPCR) demonstrated that random scaffolds (especially 600–800 nm fibers) upregulated basal keratins (KRT5, KRT14) and early differentiation markers (KRT1, KRT10, KRT4, KRT13) relative to aligned scaffolds. At the protein level, differentiation markers involucrin (IVL) and filaggrin (FLG) were likewise elevated on random scaffolds, corroborating the mRNA findings. Functional KRT5/KRT14 knockdown experiments revealed scaffold-specific dependencies: cells on random scaffolds required these keratins for viability, whereas aligned cultures remained viable upon KRT5/14 loss. Furthermore, KRT5/14 depletion differentially altered downstream differentiation markers (IVL, KRT1) and mechanotransduction markers (LMNB1, YAP1) in a scaffold-dependent manner. Collectively, these findings establish fiber orientation and diameter as key design parameters for controlling keratinocyte fate. As a translational concept, layered scaffolds combining aligned and random fibers may enable spatially controlled proliferation and differentiation in engineered oral epithelia. Full article

(This article belongs to the Special Issue Recent Advances in Regenerative Dentistry—Second Edition)

25 pages, 1855 KB

Open AccessReview

Emerging Role of TRP Channels in Osteoarthritis Pathogenesis

by Shivmurat Yadav, Jyoti Yadav and Mary Beth Humphrey

Cells 2026, 15(3), 299; https://doi.org/10.3390/cells15030299 - 5 Feb 2026

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Abstract

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, synovial inflammation, osteophyte formation, joint space narrowing, and persistent pain. During OA progression, synovial inflammation triggers the release of pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6, which activate matrix metalloproteinases (MMPs) and [...] Read more.

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, synovial inflammation, osteophyte formation, joint space narrowing, and persistent pain. During OA progression, synovial inflammation triggers the release of pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6, which activate matrix metalloproteinases (MMPs) and aggrecanases, driving extracellular matrix (ECM) degradation. Emerging evidence indicates that transient receptor potential (TRP) channels, via calcium (Ca²⁺) signaling, function as molecular sensors in joint tissues, including chondrocytes, synoviocytes, sensory neurons, and regulate cartilage homeostasis, synovial inflammation, and OA pain. In cartilage, TRP channels govern chondrocyte survival, mechanotransduction, autophagy, oxidative stress, and ECM turnover, thereby modulating cartilage homeostasis. In synovial tissue, TRP channels regulate inflammatory signaling and cytokine, chemokine, and matrix-degrading enzyme production, leading to synovitis and joint destruction. In sensory neurons innervating the joint, TRP channels respond to mechanical and inflammatory stimuli, increasing nociceptor excitability, neuropeptide release, and pain sensitization, driving OA pain. TRP channel signaling also modulates immune cell infiltration and macrophage-driven inflammation, sustaining chronic pain and tissue damage in OA. This review summarizes emerging evidence on TRP channel functions in OA pathogenesis and highlights their potential as therapeutic targets to alleviate inflammation, protect cartilage, and reduce OA-associated pain. Full article

(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels and Health and Disease)

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18 pages, 701 KB

Open AccessReview

mRNA Vaccines in Melanoma Immunotherapy—A Narrative Review

by Paulina Plewa, Maciej Ćmil, Filip Lewandowski, Agata Poniewierska-Baran and Andrzej Pawlik

Cells 2026, 15(3), 298; https://doi.org/10.3390/cells15030298 - 5 Feb 2026

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Abstract

Melanoma is one of the most aggressive forms of cancer and the leading cause of death related to skin disease. Recent years have seen a significant increase in the number of cases of this type of cancer, underscoring the need to develop effective [...] Read more.

Melanoma is one of the most aggressive forms of cancer and the leading cause of death related to skin disease. Recent years have seen a significant increase in the number of cases of this type of cancer, underscoring the need to develop effective therapeutic strategies to control it. One of the most promising research directions in this field is anticancer immunotherapy, particularly the use of vaccines aimed at enhancing the body’s cellular immunity. Among the modern methods of this type, mRNA-based vaccines are prominent, gaining increasing importance as a potential tool in cancer therapy. Their main advantages include a relatively rapid and flexible production process, low production costs, and the ability to induce both humoral and cellular immune responses. Despite their numerous advantages, therapeutic mRNA vaccines also pose a number of scientific and technological challenges. These primarily concern the stability of mRNA molecules and their effective delivery to target cells. In this context, delivery systems such as lipid nanoparticles (LNPs) play a key role, protecting mRNA from degradation and facilitating its transport into the cell cytoplasm. Alternatively, systems based on biodegradable polymers are also being developed, which can provide controlled mRNA release and additional biocompatibility. However, before therapeutic mRNA vaccines become a routine component of cancer therapy, extensive clinical trials and a thorough understanding of their mechanisms of action are necessary. This paper provides an overview of the current knowledge regarding the structure and delivery methods of therapeutic mRNA vaccines, with a particular emphasis on their use in melanoma therapy. The results of clinical trials to date are also presented and the challenges associated with implementing this form of therapy in medical practice are discussed. Full article

(This article belongs to the Special Issue mRNA Vaccines and Therapeutics in Melanoma: From Mechanisms to Cellular Impact)

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21 pages, 8233 KB

Open AccessArticle

Epithelial Dynamics of Cystogenesis in Genetic Models of Autosomal Dominant Polycystic Kidney Disease

by Mengyan Sun, Zhaohui Wu, Mingqiang Hu, Wei Luo, Xiaole Chen and Ming Ma

Cells 2026, 15(3), 297; https://doi.org/10.3390/cells15030297 - 4 Feb 2026

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Abstract

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 or PKD2, is characterized by progressive and exponential enlargement of renal and hepatic cysts. However, the epithelial dynamics that generate this growth pattern remain incompletely understood. Using Brainbow/Confetti multicolor clonal lineage [...] Read more.

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 or PKD2, is characterized by progressive and exponential enlargement of renal and hepatic cysts. However, the epithelial dynamics that generate this growth pattern remain incompletely understood. Using Brainbow/Confetti multicolor clonal lineage tracing in developmental and adult-onset ADPKD mouse models, we show that polycystin-deficient epithelial cells initiate clonal expansion at early stages of tubule dilation and continue to expand throughout cyst progression. Concurrently, cyst-lining cells undergo a progressive transition from columnar to flattened morphology, which amplifies luminal enlargement independent of cell number. Integrating these measures, we developed a mathematical model demonstrating that the combination of this clonal expansion and epithelial cell shape remodeling is sufficient to produce the exponential growth trajectory observed in ADPKD. Together, these findings define the core epithelial mechanisms that drive cyst initiation and expansion, and may provide a mathematical framework for the emergent exponential growth of cysts. Full article

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41 pages, 2626 KB

Open AccessReview

Endometriosis and Oocyte Quality: Morphological Alterations, Developmental Competence, and Modifiable Strategies for Reproductive Longevity

by Martina Contestabile, Ilaria Marzi, Calogero Mangione, Ferdinando Franzoni, Paolo Giovanni Artini and Simona Daniele

Cells 2026, 15(3), 296; https://doi.org/10.3390/cells15030296 - 4 Feb 2026

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Abstract

Endometriosis is a chronic, estrogen-dependent inflammatory disorder that is increasingly recognized as a systemic condition with profound implications for female reproductive potential. In addition to pelvic distortion and impaired folliculogenesis, growing evidence indicates that intrinsic alterations in oocyte morphology, mitochondrial function, and developmental [...] Read more.

Endometriosis is a chronic, estrogen-dependent inflammatory disorder that is increasingly recognized as a systemic condition with profound implications for female reproductive potential. In addition to pelvic distortion and impaired folliculogenesis, growing evidence indicates that intrinsic alterations in oocyte morphology, mitochondrial function, and developmental competence contribute to infertility. The disease is driven by a multifactorial interplay of somatic mutations, epigenetic remodeling, immune dysregulation, and aberrant steroid signaling, which together create a pro-inflammatory, oxidative, and fibrotic microenvironment. Elevated cytokines, reactive oxygen species, and disrupted granulosa-cell function within the follicular niche impair meiotic progression, cytoplasmic maturation, and mitochondrial integrity, potentially accelerating oocyte aging and diminishing reproductive longevity. Epigenetic and post-transcriptional disturbances—including altered DNA methylation, histone modifications, and RNA-splicing defects—further reinforce estrogen dominance, progesterone resistance, and impaired decidualization, with downstream consequences for ovarian–endometrial communication. Although morphological abnormalities have been documented in oocytes from women with endometriosis, clinical outcomes remain heterogeneous, highlighting the need for integrative models that connect molecular alterations to functional reproductive endpoints. A deeper understanding of these mechanisms is essential for identifying biomarkers of oocyte competence and modifiable strategies—ranging from nutritional optimization to reduction of environmental risk factors—in clinical care to safeguard the reproductive potential of women with endometriosis. Full article

(This article belongs to the Special Issue The Blueprint of Female Reproductive Longevity: From Ovarian Biology to Modifiable Risks and Protective Strategies)

23 pages, 819 KB

Open AccessReview

Targeting Amyloid Beta Aggregation and Neuroinflammation in Alzheimer’s Disease: Advances and Future Directions

by Ioanna Dagla, Faidon Gkikas, Evagelos Gikas and Anthony Tsarbopoulos

Cells 2026, 15(3), 295; https://doi.org/10.3390/cells15030295 - 4 Feb 2026

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly. Among the diverse pathological features of AD, amyloid beta (Aβ) aggregation and neuroinflammation are recognized as central and interlinked mechanisms driving disease progression. This review [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly. Among the diverse pathological features of AD, amyloid beta (Aβ) aggregation and neuroinflammation are recognized as central and interlinked mechanisms driving disease progression. This review focuses specifically on these two processes and highlights current pharmacological limitations in modifying disease pathology. Natural products such as curcumin, resveratrol, Ginkgo biloba, epigallocatechin gallate (EGCG), crocin, ashwagandha, and cannabidiol (CBD) have shown promising activity in modulating Aβ aggregation and neuroinflammatory pathways, offering multi-target neuroprotective effects in preclinical studies. However, their therapeutic application remains hindered by poor solubility, instability, rapid metabolism, and limited blood–brain barrier (BBB) permeability. To overcome these barriers, nanotechnology-based drug delivery systems—including polymeric nanoparticles, niosomes, solid lipid nanoparticles, and chitosan-based carriers—have emerged as effective strategies to enhance brain targeting, bioavailability, and pharmacological efficacy. We summarize the mechanistic insights and nanomedicine approaches related to these bioactives and discuss their potential in developing future disease-modifying therapies. By focusing on Aβ aggregation and neuroinflammation, this review provides a targeted perspective on the evolving role of natural compounds and nanocarriers in AD treatment. Full article

(This article belongs to the Special Issue Natural Products in Neurodegenerative Diseases: Current Trends and Future Perspectives)

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22 pages, 5775 KB

Open AccessArticle

Epitranscriptomic Regulation of Platinum Resistance via the METTL3-ADAM23 Axis in Ovarian Cancer

by Ujin Kim, Junzui Li, Daniela Matei and Hao Huang

Cells 2026, 15(3), 294; https://doi.org/10.3390/cells15030294 - 4 Feb 2026

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Abstract

N6-methyladenosine (m⁶A) has emerged as a pivotal regulator of post-transcriptional gene control, yet its contribution to chemotherapy resistance remains insufficiently defined. Here, we describe a previously unrecognized METTL3-ADAM23 epitranscriptomic regulatory relationship associated with platinum (Pt) resistance in ovarian cancer (OC). We [...] Read more.

N6-methyladenosine (m⁶A) has emerged as a pivotal regulator of post-transcriptional gene control, yet its contribution to chemotherapy resistance remains insufficiently defined. Here, we describe a previously unrecognized METTL3-ADAM23 epitranscriptomic regulatory relationship associated with platinum (Pt) resistance in ovarian cancer (OC). We show that cisplatin treatment increases global m⁶A levels and METTL3 expression, linking Pt exposure to activation of the m⁶A machinery. Functional perturbation studies demonstrate that METTL3 overexpression enhances cisplatin resistance, whereas METTL3 knockdown or pharmacologic inhibition with the selective METTL3 inhibitor STM2457 sensitizes OC cells to Pt treatment in vitro and improves Pt response in vivo. Transcriptomic profiling identifies ADAM23, a cell-adhesion-related tumor suppressor, as a METTL3-dependent, m⁶A-associated transcript, with altered mRNA expression observed across multiple experimental systems and several high-confidence predicted m⁶A sites within its transcript. Cisplatin-associated METTL3 upregulation correlates with reduced ADAM23 expression, suggesting a potential regulatory relationship that may contribute to chemoresistance. Together, these findings support a model in which METTL3-associated increases in m⁶A methylation are linked to Pt resistance, in part through modulation of ADAM23 expression, and highlight METTL3 as a potential therapeutic target in OC. Full article

(This article belongs to the Special Issue Genomics and Cellular Mechanisms in Ovarian Cancer)

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14 pages, 588 KB

Open AccessReview

The Physiological Significance of TRP and Piezo Channels as Physical Stimulus Sensors in Brown Adipocytes

by Kunitoshi Uchida and Mari Iwase

Cells 2026, 15(3), 293; https://doi.org/10.3390/cells15030293 - 4 Feb 2026

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Abstract

Most transient receptor potential (TRP) channels are Ca²⁺-permeable non-selective cation channels that function as polymodal receptors activated by a wide variety of stimuli, including natural compounds such as pungent substances, physical stimuli, lipids, intracellular signaling molecules, and ions. Their physiological roles [...] Read more.

Most transient receptor potential (TRP) channels are Ca²⁺-permeable non-selective cation channels that function as polymodal receptors activated by a wide variety of stimuli, including natural compounds such as pungent substances, physical stimuli, lipids, intracellular signaling molecules, and ions. Their physiological roles are diverse, including sensory perception, ion transport, and intracellular signaling. Similarly, Piezo channels, which are also Ca²⁺-permeable non-selective cation channels, are activated by mechanical stimuli such as membrane stretching and contribute to touch sensation, blood flow regulation, and bladder-filling sensation, among other functions. While research on non-selective cation channels in relation to energy metabolism has primarily focused on TRP channels expressed in primary afferent neurons, studies over the past decade have revealed the important roles of TRP and Piezo channels in brown adipocytes. In this review, we highlight evidence regarding the contributions of TRPV2 and Piezo1 to brown adipocyte differentiation and thermogenesis and briefly summarize recent advances regarding other TRP channels expressed in brown adipocytes. Furthermore, we propose a conceptual framework in which a “modal shift” in TRP/Piezo channels, defined as developmental stage-dependent changes in their functional properties, may contribute to the regulation of brown adipocytes’ functions. Full article

(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels and Health and Disease)

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33 pages, 26227 KB

Open AccessArticle

Engineered CCR2 Cell Membrane-Wrapped Cepharanthine Liposomes for Potential Targeted Attenuation of Acute Lung Injury

by Yifan Qing, Wenbo Zhao, Liangliang Xue, Yu Luo, Yuhao Gao, Xiang Sun, Fan Li, Linxuan Dai, Jing Mo, Guoqing Xu, Zenghao Bi, Suleixin Yang, Woo Tiam Hee, Jie Li and Liang Leng

Cells 2026, 15(3), 292; https://doi.org/10.3390/cells15030292 - 4 Feb 2026

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Abstract

Severe respiratory inflammation or viral infections can lead to acute lung injury (ALI), a disease characterized by diffuse inflammatory injury of the pulmonary epithelium and endothelium. Cepharanthine (CEP) is reported as a promising drug candidate due to its antiviral properties. However, CEP exhibits [...] Read more.

Severe respiratory inflammation or viral infections can lead to acute lung injury (ALI), a disease characterized by diffuse inflammatory injury of the pulmonary epithelium and endothelium. Cepharanthine (CEP) is reported as a promising drug candidate due to its antiviral properties. However, CEP exhibits poor solubility and low bioavailability. Therefore, we developed a novel liposome, named CEP@LP-M^CCR2, which integrates the advantages of cell membranes and lipid materials, to achieve effective accumulation of CEP in inflamed lungs. It exhibits a 1.73-fold increase in lung accumulation at 24 h in vivo, a 4.56-fold increase in cellular uptake in MLE-12 cells. CEP@LP-M^CCR2 is equipped with a CCR2-overexpressed surface, enabling it to selectively neutralize elevated levels of CCL2, which is related to ALI, thereby reducing macrophage infiltration, thereby reducing the spread of inflammation, such as a reduction in levels of key pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). CEP@LP-M^CCR2 could suppress M1 macrophage polarization, which led to a marked decrease in iNOS and an increase in Arg1. It upregulated the expression of junctional proteins E-cadherin and Occludin, indicating potential recovery of the pulmonary epithelial barrier. RNA sequencing analysis implied the potential of CEP@LP-M^CCR2 to inactivate the TNF/NF-κB signaling axis. Full article

(This article belongs to the Special Issue LPS-Induced Inflammatory Diseases)

18 pages, 2290 KB

Open AccessFeature PaperArticle

CD74-Targeted Cathepsin-Inhibitor Antibody–Drug Conjugate Triggers Apoptosis in DLBCL.

by Ihab Abd-Elrahman, Noha Khairi, Reut Sinai-Turyansky, Ivan Zlotber, Riki Perlman, Emmanuelle Merquiol, Galia Blum and Dina Ben Yehuda

Cells 2026, 15(3), 291; https://doi.org/10.3390/cells15030291 - 4 Feb 2026

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Abstract

Transcriptomic analyses of public datasets (TCGA and GTEx) revealed that both CD74 and Cathepsin L (CTSL) are significantly overexpressed in diffuse large B-cell lymphoma (DLBCL) compared to normal tissues, and that their expression levels are highly correlated to each other (Spearman R [...] Read more.

Transcriptomic analyses of public datasets (TCGA and GTEx) revealed that both CD74 and Cathepsin L (CTSL) are significantly overexpressed in diffuse large B-cell lymphoma (DLBCL) compared to normal tissues, and that their expression levels are highly correlated to each other (Spearman R = 0.64, p = 3 × 10⁻⁴⁶). Kaplan–Meier analysis showed that elevated expression of both genes is associated with reduced overall survival (OS), defining a high-risk CD74+/CTSL+ DLBCL subgroup. This is the first study demonstrating coordinated overexpression of CD74 and CTSL and proposing their dual targeting via antibody–drug conjugates (ADCs) to improve outcomes in relapsed or refractory DLBCL. Cysteine cathepsins, a family of proteases, are upregulated in many cancers, facilitating tumor invasion and metastasis. Cathepsins are overexpressed and play key roles in DLBCL progression. GB111-NH₂, a potent broad-spectrum cathepsin inhibitor, significantly reduced cathepsin activity in lymphoma cell lines and patient samples. GB111-NH₂ treatment increased apoptosis and caspase-3 activation in DLBCL patient cells and chronic lymphocytic leukemia (CLL) mononuclear cells. Here, we developed a modified cathepsin inhibitor, M-GB, containing a maleimide linker for site-specific antibody conjugation. While M-GB alone has poor cell permeability, when conjugated to an antibody, it forms an ADC (M-GB–ADC) that selectively induces lymphoma cell death. One M-GB–ADC demonstrated high specificity for CD74-expressing lymphoma cells while exhibiting minimal toxicity to non-target cells in vitro. Our findings highlight the potential of another M-GB–ADC as a targeted therapy for overcoming rituximab resistance and treatment failure in DLBCL. This strategy enhances therapeutic efficacy and represents a preclinical proof-of-concept treatment option by directing a cathepsin-inhibitor payload specifically to malignant B cells. Full article

(This article belongs to the Special Issue Novel Immunotherapies for Diffuse Large B-Cell Lymphoma)

43 pages, 8860 KB

Open AccessArticle

Integrative Proteomics Reveal Neuroimmune and Dopaminergic Alterations Across the Nociceptive Neuraxis in Neuropathic Pain

by Shreyasi Majumdar, Santosh Kumar Prajapati, Aishwarya Dande, Vinod Kumar Yata, Khushboo Choudhary, Ramalingam Peraman, Nitesh Kumar and Sairam Krishnamurthy

Cells 2026, 15(3), 290; https://doi.org/10.3390/cells15030290 - 4 Feb 2026

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Abstract

Neuropathic pain (NP) arises from maladaptive changes in peripheral and central nociceptive circuits, yet molecular alterations spanning the entire pain neuraxis remain poorly understood. Neuroinflammation is increasingly recognized as a central mechanism in NP chronification, yet the region-specific molecular events linking immune activation [...] Read more.

Neuropathic pain (NP) arises from maladaptive changes in peripheral and central nociceptive circuits, yet molecular alterations spanning the entire pain neuraxis remain poorly understood. Neuroinflammation is increasingly recognized as a central mechanism in NP chronification, yet the region-specific molecular events linking immune activation to affective pain processing remain inadequately defined. In this study, we employed high-resolution LC-HRMS-based quantitative proteomics to investigate chronic constriction injury (CCI)-induced molecular alterations in the sciatic nerve (SN), spinal cord (SC), and orbitofrontal cortex (OFC) of male Wistar rats, a region critical for affective and cognitive pain modulation. Behavioral assessments confirmed the development of NP phenotypes and motor deficits. Proteomic profiling revealed exclusive and differentially expressed proteins enriched in neuroinflammatory pathways across all regions. S100 proteins (S100A8 and S100B) were significantly elevated in SN, SC, and OFC, as confirmed by immunofluorescence. Their up-regulation coincided with increased astrocyte (GFAP) and microglial (Iba-1) activation, highlighting a pervasive inflammatory milieu. Intriguingly, the OFC proteome demonstrated marked up-regulation of dopamine-regulating proteins and positive regulation of dopaminergic neurotransmission, suggesting involvement of reward-related analgesic circuits. Together, our findings delineate a “nociceptive neuraxis” driven by neuroimmune activation and neuromodulatory adaptations that interfaces with dopaminergic signaling to influence sensory and affective components of pain. This integrative molecular map highlights potential therapeutic targets, including glial-derived S100 proteins and dopamine modulators for the comprehensive management of NP. Full article

(This article belongs to the Special Issue Neuroinflammation in Brain Health and Diseases)

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15 pages, 3739 KB

Open AccessArticle

FRY Mediates THP1-Driven Ovarian Cancer Invasion Through the PI3K/AKT Pathway

by Jin-Hyung Kim, Minjun Choi, Jae-Yoon Kim, Soo-Yeon Woo, Woo Yeon Hwang and Jung-Hye Choi

Cells 2026, 15(3), 289; https://doi.org/10.3390/cells15030289 - 3 Feb 2026

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Abstract

Ovarian cancer remains the most lethal gynecological malignancy, largely due to its early dissemination and extensive peritoneal metastasis. The tumor microenvironment (TME), particularly tumor-associated macrophages, promotes this invasive phenotype; however, the precise molecular effectors linking immune-to-tumor signaling remain unclear. We identified FRY, a [...] Read more.

Ovarian cancer remains the most lethal gynecological malignancy, largely due to its early dissemination and extensive peritoneal metastasis. The tumor microenvironment (TME), particularly tumor-associated macrophages, promotes this invasive phenotype; however, the precise molecular effectors linking immune-to-tumor signaling remain unclear. We identified FRY, a microtubule-binding protein previously uncharacterized in ovarian pathology, as a critical mediator of macrophage-driven invasion. We observed that conditioned medium from ovarian cancer-stimulated macrophages (OCM) robustly induced FRY expression in ovarian cancer cells. Clinically, elevated FRY levels correlate with advanced tumor stage and poor patient survival. Functionally, FRY knockdown significantly abrogated OCM-induced invasion without affecting cell viability, highlighting its specific role in motility. Mechanistically, FRY facilitates epithelial–mesenchymal transition (EMT) and acts as an essential downstream effector of the PI3K/AKT signaling cascade; notably, FRY was required for AKT1-driven invasive behaviors. Furthermore, we identified the transcription factor NFIX as a key regulator of FRY expression. Macrophage-derived signals upregulate NFIX, which directly regulates FRY transcription. Pharmacological inhibition of the CXCR1/2 axis with reparixin effectively blocked OCM-mediated induction of both NFIX and FRY, suggesting that chemokine signaling initiates this pro-invasive loop. Collectively, these findings suggest that FRY is a macrophage-driven mediator of invasion and underscore its potential relevance in ovarian cancer. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironments for Enhanced Cancer Immunotherapy)

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41 pages, 16972 KB

Open AccessSystematic Review

Copper, Ceruloplasmin, Zinc, and Manganese Levels in Brain and Biological Fluids from Parkinson’s Disease Patients: Systematic Review and Meta-Analysis

by Félix Javier Jiménez-Jiménez, Hortensia Alonso-Navarro, Elena García-Martín, Miguel Angel Martín-Gómez, Paula Salgado-Cámara, Alba Cárcamo-Fonfría, Margarita Arroyo-Solera and José A. G. Agúndez

Cells 2026, 15(3), 288; https://doi.org/10.3390/cells15030288 - 3 Feb 2026

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Abstract

The present systematic review and meta-analysis aims to establish whether the brain, cerebrospinal fluid (CSF), serum/plasma whole blood, urine, and hair levels of copper, ceruloplasmin, zinc, and manganese are related to the risk for Parkinson’s disease (PD). We reviewed the PubMed and Web [...] Read more.

The present systematic review and meta-analysis aims to establish whether the brain, cerebrospinal fluid (CSF), serum/plasma whole blood, urine, and hair levels of copper, ceruloplasmin, zinc, and manganese are related to the risk for Parkinson’s disease (PD). We reviewed the PubMed and Web of Science Core Collection databases from 1966 to 29 November 2025, and identified references of interest for this topic. We performed the meta-analysis of eligible studies that followed the PRISMA and MOOSE guidelines, with the R software package meta R 4.2.0 version. When compared to age- and sex-matched controls, PD patients showed decreased concentrations of copper in the substantia nigra and other brain areas, a trend towards increased CSF and decreased serum/plasma copper levels, decreased serum/plasma ceruloplasmin levels, decreased zinc levels in serum/plasma and increased zinc in whole blood and hair, and increased hair manganese levels. These results suggest an association between these transition metals and risk for PD. Full article

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20 pages, 9732 KB

Open AccessArticle

Identification of Natural Compounds Triggering MRGPRX2-Mediated Calcium Flux and Degranulation in RBL-2H3 Cells

by Lihui Zhang, Jing Liu, Jian Zheng, Wenguang Jing, Wenjuan Zhang, Jia Chen, Xinyue Zhang, Xianlong Cheng and Feng Wei

Cells 2026, 15(3), 287; https://doi.org/10.3390/cells15030287 - 3 Feb 2026

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Abstract

Natural compounds have experienced increasing clinical application, but their association with rapid-onset anaphylactoid reactions (ARs) present a significant challenge to their safe use. These ARs, clinically resembling Type I hypersensitivity, are non-IgE-mediated and involve direct mast cell activation, primarily through the human Mas-related [...] Read more.

Natural compounds have experienced increasing clinical application, but their association with rapid-onset anaphylactoid reactions (ARs) present a significant challenge to their safe use. These ARs, clinically resembling Type I hypersensitivity, are non-IgE-mediated and involve direct mast cell activation, primarily through the human Mas-related G protein-coupled receptor X2 (MRGPRX2). We computationally screened a natural compound library for MRGPRX2 activation. A human MRGPRX2-expressing cell model was established. Cell viability assays (0–80 μM) were performed to determine appropriate drug concentrations. Compared to the controls, Baohuoside I (10 μM), along with Kaempferol-3-O-rutinoside, Epigallocatechin gallate (EGCG), Isochlorogenic Acid B, Baicalin, Andrographolide, Isorhamnetin, and Dehydroandrographolide (all at 20 μM), significantly increased intracellular calcium flux (p < 0.05) and boosted tryptase and β-hexosaminidase secretion (ELISA) (p < 0.05) in mast cells. Furthermore, the degranulation induced by these compounds was inhibited by the MRGPRX2 inhibitor Z3578 at 20 μM. Neutral red staining was employed to observe cellular morphological changes. Specific compounds capable of mediating ARs through MRGPRX2 activation on mast cells were identified. This contributes to safer and more effective drug use by elucidating the potential triggers of ARs. Full article

(This article belongs to the Special Issue Cellular and Molecular Insights into Allergies and Allergic Diseases)

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22 pages, 4698 KB

Open AccessArticle

Neuroimmune Activation in a Goat Model of Intervertebral Disc Degeneration

by Janai A. Augustin, Kevin G. Burt, Caitlin Barrett, Matthew Fainor, Brianna S. Orozco, Thomas P. Schaer, Harvey E. Smith, Robert L. Mauck and Sarah E. Gullbrand

Cells 2026, 15(3), 286; https://doi.org/10.3390/cells15030286 - 3 Feb 2026

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Abstract

Intervertebral disc degeneration (IVDD) initiates a cascade of structural and biological changes that compromise mechanical function, often leading to chronic pain. While small animal models have provided insight into inflammatory and nociceptive mechanisms of IVDD, translational studies require large animal models that more [...] Read more.

Intervertebral disc degeneration (IVDD) initiates a cascade of structural and biological changes that compromise mechanical function, often leading to chronic pain. While small animal models have provided insight into inflammatory and nociceptive mechanisms of IVDD, translational studies require large animal models that more closely replicate human spine anatomy and physiology. This study induced cervical disc degeneration via intradiscal chondroitinase ABC (ChABC) injection in a large animal model and evaluated the associated disc pathology and neuroinflammatory responses across IVDs and within spinal cord and dorsal root ganglia (DRG) tissues. Results confirmed structural degeneration at ChABC-injected levels and revealed additional evidence of adjacent segment degeneration. Neuroinflammatory analyses revealed innervation, via deposition of PGP9.5 and NFH, throughout both ChABC-injected and adjacent IVDs. Monocyte markers were significantly increased in ChABC-degenerated IVDs. Across experimental groups, the level of monocyte (Ly6C) and macrophage (CD68) markers correlated with worsened histological scores and with reduced mechanical integrity. Similarly, increased production of the neuropeptide, Substance P, in IVDs was significantly positively correlated with compromised IVD mechanical function. Finally, we observed elevated production of the microglia marker, Iba1, and Substance P production in the spinal cord, with similar trends in DRGs, in degenerative spines. By establishing quantitative relationships between disc pathology, immune responses, and neural activation, this work established possible disease-contributing neuroinflammatory activation and further validated a clinically relevant model for preclinical evaluation of regenerative and therapeutic strategies. Full article

(This article belongs to the Special Issue Novel Insights into Mechanism and Treatment of Degenerative Disc Disease)

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17 pages, 1818 KB

Open AccessArticle

Targeting the c-Met/VEGFR Pathway to Boost Nab-Paclitaxel Efficacy in Gastric Cancer: Preclinical Insights

by Jennifer Huang, Quinn Kaurich, Md Sazzad Hassan, Urs von Holzen and Niranjan Awasthi

Cells 2026, 15(3), 285; https://doi.org/10.3390/cells15030285 - 3 Feb 2026

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Abstract

Combination chemotherapy regimens are commonly employed to treat advanced gastric adenocarcinoma (GAC), yet median survival remains less than one year. Nab-paclitaxel has demonstrated significant antitumor activity in preclinical GAC models. Overexpression of growth factors and their receptors is prevalent in GAC and [...] Read more.

Combination chemotherapy regimens are commonly employed to treat advanced gastric adenocarcinoma (GAC), yet median survival remains less than one year. Nab-paclitaxel has demonstrated significant antitumor activity in preclinical GAC models. Overexpression of growth factors and their receptors is prevalent in GAC and contributes to its pathophysiology, with aberrant activation of the HGF/c-Met pathway reported in up to 50% of patients. We hypothesized that merestinib, a small-molecule inhibitor of c-Met, Axl, and DDR1/2, would enhance the therapeutic response to nab-paclitaxel in GAC. In high c-Met–expressing MKN-45 peritoneal dissemination xenografts in female NOD/SCID mouse models, animal survival was 17 days in controls, 37 days with nab-paclitaxel (118% increase), 24 days with merestinib (41% increase), and 43 days with the combination (153% increase), demonstrating significantly enhanced survival compared with either monotherapy. In MKN-45 subcutaneous xenografts, tumor volumes in the control, nab-paclitaxel, merestinib, and combination groups were 503 mm³, 115 mm³, 91 mm³, and −9.7 mm³ (indicating tumor regression), respectively. In low c-Met-expressing SNU-1 xenografts, tumor volumes were 219 mm³, 105 mm³, 131 mm³, and 57 mm³, respectively. IHC analysis of tumor cell proliferation and microvessel density in MKN-45 tumors supported these findings. In vitro, nab-paclitaxel and merestinib each reduced cell proliferation in GAC-associated cells, with enhanced inhibitory effects when used in combination. In MKN-45 cells, merestinib increased the expression of pro-apoptotic proteins and decreased phosphorylation of c-Met, EGFR, IGF-1R, ERK, and AKT. These results indicate that combining merestinib with nab-paclitaxel may represent a promising therapeutic strategy to improve outcomes for patients with GAC. Full article

(This article belongs to the Special Issue Gastrointestinal Cancer: From Cellular and Molecular Mechanisms to Therapeutic Opportunities)

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21 pages, 3180 KB

Open AccessArticle

Stress-Inducible Transcription Factor NUPR1 Is Involved in the Inhibitory Effects Exerted by Statins on Insulin Action in ER-Positive Breast Cancer Cells

by Domenica Scordamaglia, Azzurra Zicarelli, Francesca Cirillo, Marianna Talia, Ernestina Marianna De Francesco, Roberta Malaguarnera, Marcello Maggiolini and Rosamaria Lappano

Cells 2026, 15(3), 284; https://doi.org/10.3390/cells15030284 - 2 Feb 2026

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Abstract

Obesity is frequently associated with metabolic alterations like hypercholesterolemia and hyperinsulinemia and represents a major risk factor for several diseases, including breast cancer (BC). Insulin signaling, as well as the frequent overexpression of the insulin receptor (IR), play a key role in BC [...] Read more.

Obesity is frequently associated with metabolic alterations like hypercholesterolemia and hyperinsulinemia and represents a major risk factor for several diseases, including breast cancer (BC). Insulin signaling, as well as the frequent overexpression of the insulin receptor (IR), play a key role in BC progression. Emerging evidence suggests that the widely prescribed lipid-lowering drugs, named statins, may reduce the risk of recurrence and blunt BC cell proliferation, mainly inhibiting the HMGCR-dependent activation of the mevalonate pathway. In this study, we investigated the effects of simvastatin, atorvastatin and rosuvastatin in BC cells stimulated by insulin. To this end, we used as a BC model system MCF7 cells and naturally immortalized BCAHC-1 cells, which are characterized by high IR-expression levels. Our investigation demonstrates that statins reduce the proliferation and clonogenic capacity of BC cells prompted by insulin treatment. Mechanistically, statins impair the IR-mediated signaling and downregulate the stress-inducible transcription factor NUPR1, a known regulator of cancer progression. Importantly, NUPR1 inhibition blunted the stimulatory action of insulin on BC cells. Consistent with these findings, survival analyses of large cohorts of patients revealed that high levels of NUPR1 are associated with poor BC prognosis. Overall, our results provide novel mechanistic evidence supporting the repositioning of statins in BC, particularly in tumors characterized by elevated IR expression and activity. Full article

(This article belongs to the Special Issue Biomarkers in Breast Cancer)

19 pages, 4511 KB

Open AccessArticle

SATB2 Induces Malignant Transformation and Cancer Stem Cell Characteristics, and Inhibition of Its Expression Reverses Drug Resistance in Mesothelioma

by Cynthia Brown, Shivam Srivastava, Rohit Srivastava, Rashmi Srivastava, Jason Morvant, Anju Shrivastava and Rakesh K. Srivastava

Cells 2026, 15(3), 283; https://doi.org/10.3390/cells15030283 - 2 Feb 2026

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Abstract

SATB2 (special AT-rich binding protein 2) functions as a chromatin-associated epigenetic regulator that modulates gene expression, in part by serving as a transcriptional cofactor. This study assessed whether SATB2 overexpression is sufficient to promote in vitro transformation of human mesothelial cells and whether [...] Read more.

SATB2 (special AT-rich binding protein 2) functions as a chromatin-associated epigenetic regulator that modulates gene expression, in part by serving as a transcriptional cofactor. This study assessed whether SATB2 overexpression is sufficient to promote in vitro transformation of human mesothelial cells and whether SATB2 suppression in mesothelioma cancer stem cell (CSC)–enriched populations is associated with altered chemoresistance. SATB2 expression was high in human malignant pleural mesothelioma (MPM) cell lines but absent in Met5A mesothelial cells. Ectopic SATB2 expression in Met5A cells was associated with acquisition of malignant and stem cell–like phenotypes, including increased expression of stem cell markers and pluripotency-associated factors, as well as anchorage-independent growth in soft agar and spheroid formation in suspension culture. In contrast, Met5A cells transduced with an empty vector did not form colonies or mesospheres. SATB2 overexpression in Met5A cells was also associated with increased motility, migration, and invasion, accompanied by induction of epithelial–mesenchymal transition (EMT)–related transcription factors relative to empty vector controls. Conversely, shRNA-mediated SATB2 knockdown in an MPM cell line attenuated proliferation, EMT-associated features, and CSC-like characteristics. Chromatin immunoprecipitation assays identified SATB2 occupancy at promoter regions of Bcl2, XIAP, KLF4, c-Myc, NANOG, and SOX2, consistent with a role in transcriptional regulation of genes linked to transformation, pluripotency, cell survival, proliferation, and EMT. In CSC-enriched cells, SATB2 inhibition was associated with increased sensitivity to cisplatin and pemetrexed, concomitant with reduced OCT4 and SOX2 expression. Collectively, these findings support SATB2 as a candidate therapeutic target in MPM and suggest that SATB2 suppression may enhance chemotherapy response when combined with standard agents. Full article

(This article belongs to the Special Issue The Function of Stem Cells in the Biomedical Applications)

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18 pages, 3407 KB

Open AccessArticle

SMG6’s PIN (PilT N-Terminus) Domain Is Required for Nonsense-Mediated mRNA Decay (NMD) In Vivo

by Baihui Chai, Xiao Tan, Yan Li, Chengyan Chen, Xin Ma and Tangliang Li

Cells 2026, 15(3), 282; https://doi.org/10.3390/cells15030282 - 2 Feb 2026

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Abstract

Nonsense-mediated mRNA decay (NMD) is a highly conserved RNA quality and quantity surveillance machinery in eukaryotic cells, serving as an important node in the post-transcriptional gene expression. Previous studies using the complete knockout of individual NMD factors in cells or animals reveal that [...] Read more.

Nonsense-mediated mRNA decay (NMD) is a highly conserved RNA quality and quantity surveillance machinery in eukaryotic cells, serving as an important node in the post-transcriptional gene expression. Previous studies using the complete knockout of individual NMD factors in cells or animals reveal that NMD deficiency causes developmental defects and compromises tissue homeostasis. However, because most NMD factors participate in multiple molecular functions, a direct link between NMD and cell fate determination is missing. SMG6 is a core NMD effector and the only endoribonuclease among all NMD factors. The NMD function of SMG6 is exclusively mediated by its PIN (PilT N-terminus) domain. In this study, we engineered a mouse model with the capability of specifically deactivating the SMG6’s PIN domain/endoribonuclease activity (Smg6-PIN^F/F), but not knocking out the complete SMG6 protein. We found that SMG6’s PIN domain is essential for NMD activity in embryonic stem cells (ESCs) and various tissues of adult mice. Furthermore, loss of SMG6’s PIN domain is dispensable for the mouse ESC self-renewal, but severely compromises the differentiation, which consequently causes the mutant mice to die during the process of organogenesis. Through the induced deletion of SMG6’s PIN domain in adult mice, we found that loss of SMG6’s NMD function affects the homeostasis of several mouse tissues, including the testis and the intestine. In sum, our study establishes a mechanistic link between NMD per se and cell fate determination of mouse ESCs, as well as in the tissues of adult mice, where cell fate transitions are actively ongoing. The Smg6-PIN^F/F mouse line could be a valuable strain for elucidating the biology of NMD per se. Full article

(This article belongs to the Special Issue Post-Transcriptional Control of Stem Cell Fate and Neural Development)

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Cells, Volume 15, Issue 3 (February-1 2026) – 100 articles

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