Cells

25 pages, 22191 KB

Open AccessArticle

The NF-κB Isoform p65 iso5 Is Associated with Distinct Transcriptional Programs and Signaling Pathways

by Gaetano Spinelli, Ilaria Cosentini, Giuseppa Biddeci, Judit Mihaly-Bison, Gioacchin Iannolo, Giovanni Duro, Carmela Zizzo, Paolo Colomba, Johannes A. Schmid and Francesco Di Blasi

Cells 2026, 15(18), 1643; https://doi.org/10.3390/cells15181643 - 10 Sep 2026

Abstract

NF-κB p65 (RelA) is a key regulator of inflammation, immunity, and stress responses. Recent evidence indicates that alternative p65 isoforms may diversify NF-κB signaling, but their functions remain largely unexplored. We previously identified a novel splice variant, p65 iso5, which contains an additional [...] Read more.

NF-κB p65 (RelA) is a key regulator of inflammation, immunity, and stress responses. Recent evidence indicates that alternative p65 isoforms may diversify NF-κB signaling, but their functions remain largely unexplored. We previously identified a novel splice variant, p65 iso5, which contains an additional upstream exon and displays distinct molecular properties, including the ability to interact with dexamethasone in a glucocorticoid receptor-dependent manner. Here, we define the transcriptional programs regulated by p65 iso5 using RNA-seq analysis of HeLa cells expressing either p65 iso5 or canonical p65, with or without dexamethasone treatment. Under basal conditions, p65 iso5 expression was associated with reduced expression of genes involved in type I interferon and antiviral pathways as compared to the effects of canonical p65, while genes involved in translation, ribosome biogenesis, and metabolic activity were not reduced as with p65. Upon dexamethasone stimulation, p65 iso5 expression was associated with extensive transcriptome remodeling characterized by suppression of biosynthetic and proliferative programs and activation of metabolic and stress-adaptive pathways. Comparative analyses reveal that glucocorticoid responses are strongly isoform-dependent, with p65 iso5 expression being associated with distinct gene expression networks supported by distinct protein–protein interaction hubs. p65 iso5 is overexpressed in cirrhotic and hepatocellular carcinoma tissues as well as in high-grade colon tumors, suggesting clinical relevance. Our findings identify p65 iso5 as a context-dependent NF-κB modulator with unique transcriptional and metabolic functions and potential relevance in inflammation-associated diseases and cancer. Full article

(This article belongs to the Special Issue NF-κB Signaling in Inflammation: Molecular Mechanisms and Therapeutic Targets)

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37 pages, 4039 KB

Open AccessReview

Biological Insights into Intestinal Adaptation from Preclinical Models of Short Bowel Syndrome

by Cesare Pane, Pierluigi Puca, Miriam Di Mattia, Sara Troisi, Marianna Kashyrina, Marco Pizzoferrato, Letizia Masi, Laura Parisio, Maria Cristina De Rosa, Beatrice Scagnoli, Marcello Chieppa, Valentina Petito, Loris Riccardo Lopetuso, Franco Scaldaferri and Alfredo Papa

Cells 2026, 15(18), 1642; https://doi.org/10.3390/cells15181642 - 10 Sep 2026

Abstract

Short bowel syndrome is a rare and clinically heterogeneous condition resulting from extensive intestinal resections or functional impairment, leading to malabsorption, fluid and electrolyte losses, and potential progression to intestinal failure requiring long-term parenteral nutrition. The long-term outcome of SBS is largely determined [...] Read more.

Short bowel syndrome is a rare and clinically heterogeneous condition resulting from extensive intestinal resections or functional impairment, leading to malabsorption, fluid and electrolyte losses, and potential progression to intestinal failure requiring long-term parenteral nutrition. The long-term outcome of SBS is largely determined by intestinal adaptation, a progressive physiological response involving epithelial remodeling, intestinal stem cell expansion, lineage-specific proliferation, vascular remodeling, and the activity of trophic mediators—most notably glucagon-like peptide-2 (GLP-2)—whose clinical relevance is exemplified by teduglutide. Despite significant therapeutic advances, the mechanisms underlying adaptation remain incompletely understood, and preclinical models are essential tools for addressing this gap. In vitro systems—including Caco-2 epithelial cultures, intestinal organoids and enteroids, and tissue-engineered intestinal constructs—enable pathway-specific mechanistic investigation and hold promise as regenerative platforms. Murine surgical models of small bowel resection and ileocecal resection provide an integrated in vivo context for dissecting cellular and molecular mechanisms of adaptation. Large animal models, particularly minipig platforms, offer anatomical and physiological proximity to humans required for translational and therapeutic evaluation. In this narrative review, we provide an updated overview of these preclinical systems, critically examining their respective strengths, limitations, and translational relevance to advance the understanding of intestinal adaptation and inform the development of more effective therapeutic strategies for SBS (graphical abstract). Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gastrointestinal Diseases)

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27 pages, 881 KB

Open AccessReview

Consolidated Evidence and New Frontiers of Liquid Biopsy in Lung Cancer: A Narrative Review

by Ornella Cantale, Alessandro Nepote, Elisa Lombardi, Federica Benso, Tommaso Trisciuoglio, Angela Listì, Francesca Bersani, Riccardo Taulli, Luisella Righi and Francesco Passiglia

Cells 2026, 15(18), 1641; https://doi.org/10.3390/cells15181641 - 10 Sep 2026

Abstract

Emerging liquid biopsy platforms are expanding frontiers in lung cancer care, facilitating real-time molecular insights and addressing some of the limitations of tissue biopsy. While standardization and sensitivity improvements are undergoing continuous refinement in those liquid biopsy techniques that are now established, several [...] Read more.

Emerging liquid biopsy platforms are expanding frontiers in lung cancer care, facilitating real-time molecular insights and addressing some of the limitations of tissue biopsy. While standardization and sensitivity improvements are undergoing continuous refinement in those liquid biopsy techniques that are now established, several advancements are expanding the panorama of its potential future applications. This review offers an overview of the emerging uses of liquid biopsy in the field of lung cancer, with a specific focus on emerging technologies. We comprehensively reviewed the literature through PubMed and Embase, combining keywords and Medical Subject Headings (MeSH) related to small-cell (SCLC) and non-small-cell lung cancer (NSCLC) and liquid biopsy using Boolean operators. The search was limited to publications from 2017 up to 2026. Titles and abstracts underwent manual scrutiny for relevance. We critically analyzed a body of evidence assessing the potential role of liquid biopsy in common and uncommon applications, such as its combination with machine learning and AI and its integration in multiomics approaches or its usage in next-generation technologies—including label-free CTC isolation, DNA fragmentomics and end-motif profiling, four-dimensional proteomics, and unconventional biospecimens—that remain largely unaddressed in prior narrative reviews on this topic. Full article

(This article belongs to the Special Issue Advances in Liquid Biopsy for Early Detection and Monitoring of Cancer)

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41 pages, 962 KB

Open AccessReview

Dietary Modulation of microRNAs as a Potential Nutritional Strategy in Inflammatory and Autoimmune Skin Diseases: A Narrative Review

by Anna Czaplicka, Klaudia Dopytalska, Maciej Dawid, Elżbieta Szymańska and Irena Walecka

Cells 2026, 15(18), 1640; https://doi.org/10.3390/cells15181640 - 10 Sep 2026

Abstract

Inflammatory and autoimmune skin diseases like psoriasis, atopic dermatitis, and hidradenitis suppurativa present significant therapeutic challenges due to their complex immunological and environmental pathogenesis. This review highlights the critical role of microRNAs (miRNAs) as epigenetic regulators of inflammatory processes and investigates the potential [...] Read more.

Inflammatory and autoimmune skin diseases like psoriasis, atopic dermatitis, and hidradenitis suppurativa present significant therapeutic challenges due to their complex immunological and environmental pathogenesis. This review highlights the critical role of microRNAs (miRNAs) as epigenetic regulators of inflammatory processes and investigates the potential of nutrigenomics to modulate their expression. Bioactive dietary components—including polyphenols such as quercetin, resveratrol, and curcumin, alongside vitamins C and D, selenium, and omega-3 fatty acids—demonstrate the ability to alter miRNA profiles like miR-21, miR-146a, and miR-155. These miRNA alterations may contribute to the regulation of key inflammatory pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK), thereby potentially influencing pro-inflammatory cytokine production and keratinocyte proliferation. However, the extent to which individual dietary compounds directly mediate effects on these pathways through miRNA regulation varies and is often supported mainly by preclinical evidence. Clinical data suggests that dietary interventions, such as weight loss and the Mediterranean diet alleviate skin symptoms and lower systemic inflammatory markers. Identifying disease-specific miRNA expression profiles represents an emerging research avenue that may, following analytical and clinical validation, inform future approaches in dermatology. Full article

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20 pages, 22376 KB

Open AccessArticle

Circulating Soluble Thrombomodulin Is Elevated in Early-Stage CKD and Is Associated with Renal Dysfunction: A Transcriptomic and Retrospective Cohort Study

by Jiao Wang, Yongfen Xiong, Chengyu Liu, Shun Wang and Wenli Wu

Cells 2026, 15(18), 1639; https://doi.org/10.3390/cells15181639 - 10 Sep 2026

Abstract

Chronic kidney disease (CKD) is characterized by progressive renal dysfunction and endothelial injury. Thrombomodulin (TM), encoded by the THBD gene, is released into the circulation as soluble TM (sTM) following endothelial damage; however, its clinical significance in CKD remains unclear. To address this [...] Read more.

Chronic kidney disease (CKD) is characterized by progressive renal dysfunction and endothelial injury. Thrombomodulin (TM), encoded by the THBD gene, is released into the circulation as soluble TM (sTM) following endothelial damage; however, its clinical significance in CKD remains unclear. To address this question, public bulk and single-cell transcriptomic datasets were analyzed to characterize THBD expression and cellular localization in kidney injury, and a retrospective cohort of 278 hospitalized patients was used to evaluate circulating sTM levels across CKD stages and their associations with renal function, coagulation, and cardiac biomarkers. The transcriptomic analyses showed that THBD was upregulated in injured kidneys, positively correlated with a fibrosis-related transcriptional signature, and predominantly expressed in renal endothelial cells. Consistent with these findings, circulating sTM was elevated as early as stage 1 CKD and increased progressively with advancing disease stage. Higher sTM levels were positively associated with serum creatinine, serum urea, and urinary albumin-to-creatinine ratio (UACR), and inversely associated with estimated glomerular filtration rate (eGFR). In addition, sTM showed weak-to-modest associations with coagulation, fibrinolytic, and cardiac biomarkers. Multivariable analysis showed that eGFR remained independently associated with log-transformed sTM after adjustment for major clinical covariates (β = −0.0116, 95% CI −0.0141 to −0.0090, p < 0.001). ROC analysis showed that sTM discriminated CKD from non-CKD (AUC = 0.971) and early-stage CKD from non-CKD (AUC = 0.854), outperforming eGFR (AUC 0.920 and 0.565, respectively) and performing comparably to UACR. Collectively, these findings support sTM as a candidate biomarker associated with CKD severity whose interpretation should integrate endothelial injury and reduced renal elimination and prospective validation is warranted. Full article

(This article belongs to the Special Issue Metabolic Reprogramming in Organ Fibrosis and Regeneration)

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19 pages, 2744 KB

Open AccessReview

The Murine Epithelial Thymic Microenvironment Is Governed by Eph/Ephrin Signalling

by Sara Montero-Herradón, David Alfaro, Agustín G. Zapata and Javier García-Ceca

Cells 2026, 15(18), 1638; https://doi.org/10.3390/cells15181638 - 10 Sep 2026

Abstract

Although the relevance of thymic epithelial cell–thymocyte interactions for thymus function has long been emphasised, the mechanisms that govern the biology of thymic epithelial cells (TECs) are not fully understood. In other epithelial tissues, erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their ligands, the [...] Read more.

Although the relevance of thymic epithelial cell–thymocyte interactions for thymus function has long been emphasised, the mechanisms that govern the biology of thymic epithelial cells (TECs) are not fully understood. In other epithelial tissues, erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their ligands, the Eph receptor-interacting proteins (ephrins), have been demonstrated to be important regulators of epithelial homeostasis. Accordingly, we have studied the function of Eph/ephrin signalling in the organisation, phenotypes and function of mouse thymic epithelial cells, as well as its effects on T-cell differentiation, for over 20 years. This review provides a detailed description of these results, concluding that the absence of certain EphA/B receptors or ephrins B generates specific phenotypes that affect T-cell differentiation and immunological function in different ways. This suggests that the proper histological organisation of the epithelial thymic stroma is not essential for normal T-cell maturation, or that at least some aspects of the process are preserved. Full article

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25 pages, 12570 KB

Open AccessReview

Biomarker-Driven Strategies for Stromal Reprogramming in Pancreatic Ductal Adenocarcinoma

by Maria De Luca, Francesco Balestra, Giorgia Panzetta, Gianluigi Giannelli and Maria Principia Scavo

Cells 2026, 15(18), 1637; https://doi.org/10.3390/cells15181637 - 10 Sep 2026

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal, partly because its dense, heterogeneous stroma restricts drug delivery, promotes immune exclusion, and supports therapeutic resistance. Stromal targeting has, therefore, evolved from broad depletion towards biomarker-guided reprogramming and normalization strategies that aim to restore vascular function, [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal, partly because its dense, heterogeneous stroma restricts drug delivery, promotes immune exclusion, and supports therapeutic resistance. Stromal targeting has, therefore, evolved from broad depletion towards biomarker-guided reprogramming and normalization strategies that aim to restore vascular function, improve intratumoral drug penetration, and enhance antitumor immunity. This review summarizes evidence on stromal biomarkers with prognostic or predictive value, including tumor–stroma ratio, fibrosis burden, cancer-associated fibroblast states, extracellular matrix stiffness, vascular accessibility, and spatial immune features. It also examines emerging therapeutic approaches to reprogram the PDAC stroma, such as repurposed drugs, immune–stromal modulators, metabolic interventions, and advanced delivery systems. Emphasis is placed on clinically or translationally supported strategies, including CXCR4, CD40, CD73, vitamin D receptor agonism, matrix remodeling, and biomarker-driven stratification. Overall, PDAC stroma is a dynamic therapeutic target, requiring composite biomarkers and rational combinations with chemotherapy, immunotherapy, and delivery-enhancing strategies. Full article

(This article belongs to the Special Issue Role of Extracellular Matrix in Cancer and Disease)

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2 pages, 157 KB

Open AccessCorrection

Correction: Maylin et al. Therapeutic Exploitation of Neuroendocrine Transdifferentiation Drivers in Prostate Cancer. Cells 2024, 13, 1999

by Zoe R. Maylin, Christopher Smith, Adam Classen, Mohammad Asim, Hardev Pandha and Yuzhuo Wang

Cells 2026, 15(18), 1636; https://doi.org/10.3390/cells15181636 - 10 Sep 2026

Abstract

In the original publication [...] Full article

2 pages, 152 KB

Open AccessComment

Implication of Sulfatide in Type 1 Diabetes and Multiple Sclerosis. Comment on Root-Bernstein, R. Type 1 Diabetes-Associated Autoantibodies, Sera and T-Cell Receptor Sequences Recognize Myelin Basic Protein: A Novel Peripheral Diabetic Neuropathy–Multiple Sclerosis Connection. Cells 2026, 15, 1384

by Rikke Thea and Karsten Buschard

Cells 2026, 15(18), 1635; https://doi.org/10.3390/cells15181635 - 10 Sep 2026

Abstract

An interesting article by Root-Bernstein [...] Full article

16 pages, 1632 KB

Open AccessArticle

The Development of Cellular Aging Models Based on AD-MSCs

by Natalia V. Elizova, Ivan V. Zhivodernikov, Vyacheslav S. Vasilyev, Yaroslav D. Tolkachev, Yuliya V. Markina, Alexander M. Markin and Tatiana V. Kirichenko

Cells 2026, 15(18), 1634; https://doi.org/10.3390/cells15181634 - 9 Sep 2026

Abstract

Cellular senescence of adipose tissue-derived mesenchymal stromal cells (AD-MSCs) is associated with chronic low-grade inflammation, metabolic dysfunction, and impaired adipogenesis contributing to the development of obesity, insulin resistance, and the progression of age-associated diseases. The aim of this study was to develop a [...] Read more.

Cellular senescence of adipose tissue-derived mesenchymal stromal cells (AD-MSCs) is associated with chronic low-grade inflammation, metabolic dysfunction, and impaired adipogenesis contributing to the development of obesity, insulin resistance, and the progression of age-associated diseases. The aim of this study was to develop a model of cellular aging based on AD-MSCs to study the senolytic efficacy of the natural fisetin preparation for the subsequent development of geroprotective therapeutic strategies. The senescent markers SA-β-gal, SASP factors, and cell cycle arrest markers p16, p21, and p53 were assessed in models of replicative and stress-induced aging of AD-MSCs. H₂O₂ was identified as the most effective inducer of AD-MSC cellular senescence in comparison with LPS. It has been shown in the model of H₂O₂-induced senescence of AD-MSCs that the proportion of SA-β-gal+ cells was 2.0 (0.7)% in non-stimulated AD-MSCs, 81.7 (12.1)% in H₂O₂-stimulated AD-MSCs, and 19.1 (5.2)% and 13.0 (3.2)% after short-term (24 h) and long-term (7 days) fisetin treatment, respectively, indicating that fisetin treatment was associated with a lower proportion of SA-β-gal+ cells. Fisetin treatment resulted in a statistically significant decrease in the secretion of MCP-1, especially during long-term incubation. IL-1β showed a significant decrease after 7 days of fisetin treatment compared to H₂O₂, but the effect at 24 h was only significant in the group of 7 days of fisetin treatment. Fisetin treatment was also associated with higher p53 and p21 concentrations. Thus, in the present study, a model of H₂O₂-induced cellular senescence of AD-MSCs was developed, which can be used to evaluate the geroprotective potential of senotherapeutic preparations; fisetin warrants further evaluation as a potential senotherapeutic agent in this model. Full article

(This article belongs to the Special Issue Modulation of Senescence and Differentiation in Human Mesenchymal Stem Cells)

17 pages, 1476 KB

Open AccessArticle

Supraphysiological Testosterone Differentially Regulates Aortic Atheroma and Cardiac Remodelling in the Testicular Feminised Mouse

by Daniel M. Kelly, Joanne E. Nettleship, Marta M. Gillett and T. Hugh Jones

Cells 2026, 15(18), 1633; https://doi.org/10.3390/cells15181633 - 9 Sep 2026

Abstract

The cardiovascular actions of testosterone remain controversial, particularly regarding the safety of testosterone replacement therapy (TTh) in hypogonadal men. We investigated the effects of sustained supraphysiological testosterone exposure on aortic atherogenesis and cardiac remodelling in the testicular feminised (Tfm) mouse, a model of [...] Read more.

The cardiovascular actions of testosterone remain controversial, particularly regarding the safety of testosterone replacement therapy (TTh) in hypogonadal men. We investigated the effects of sustained supraphysiological testosterone exposure on aortic atherogenesis and cardiac remodelling in the testicular feminised (Tfm) mouse, a model of functional androgen receptor (AR) deficiency. Male Tfm mice and AR-intact XY littermate controls were fed a cholesterol-enriched diet for 28 weeks and received fortnightly intramuscular injections of saline or supraphysiological testosterone, alone or in combination with fulvestrant (oestrogen receptor antagonist) or anastrozole (aromatase inhibitor). Aortic lipid deposition was quantified by Oil Red O staining, while cardiac remodelling was assessed by heart weight, cardiomyocyte cross-sectional area and myocardial gene expression. Supraphysiological testosterone significantly reduced aortic fatty streak formation in Tfm mice compared with saline-treated controls (1.25 ± 0.36% vs. 2.85 ± 0.37%, p < 0.01), an effect preserved following fulvestrant or anastrozole treatment, consistent with mechanisms that do not require classical AR or oestrogen receptor signalling. No additional reduction in aortic lipid deposition was observed in AR-intact XY littermates. In contrast, supraphysiological testosterone increased heart weight, cardiomyocyte size and expression of hypertrophic markers exclusively in XY mice, with no evidence of cardiac remodelling in Tfm mice. Collectively, these findings demonstrate divergent tissue-specific cardiovascular actions of testosterone, whereby supraphysiological exposure promotes AR-dependent cardiac remodelling without conferring additional vascular benefit, supporting maintenance of physiological testosterone concentrations during TTh. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Testosterone in Metabolic Disorders)

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20 pages, 15783 KB

Open AccessArticle

ALDH2 Deficiency Promotes Mammary Epithelial Stemness and Proliferative Morphogenesis Through Oxidative Stress, RANKL Induction, and Estrogen Receptor Signaling

by Zhikun Ma, Amanda B. Parris, Miles Lester, De’ja Gissendanner, Vasilis Vasiliou and Xiaohe Yang

Cells 2026, 15(18), 1632; https://doi.org/10.3390/cells15181632 - 9 Sep 2026

Abstract

Alcohol consumption is associated with increased breast cancer risk, partly due to the accumulation of toxic aldehydes like acetaldehyde, a carcinogenic byproduct of ethanol metabolism. Acetaldehyde Dehydrogenase 2 (ALDH2), a key mitochondrial enzyme, detoxifies acetaldehyde and other reactive aldehydes that drive oxidative stress, [...] Read more.

Alcohol consumption is associated with increased breast cancer risk, partly due to the accumulation of toxic aldehydes like acetaldehyde, a carcinogenic byproduct of ethanol metabolism. Acetaldehyde Dehydrogenase 2 (ALDH2), a key mitochondrial enzyme, detoxifies acetaldehyde and other reactive aldehydes that drive oxidative stress, DNA damage, and hormonal dysregulation—processes central to carcinogenesis. Although alcohol consumption has been implicated in breast cancer, the role of ALDH2 deficiency itself, in the absence of exogenous alcohol exposure, in mammary gland biology and cancer susceptibility remains unclear. Genetic variants that impair ALDH2 activity are highly prevalent in East Asian populations, where carriers of inactive ALDH2 alleles exhibit impaired aldehyde detoxification. While such individuals are more susceptible to alcohol-related cancers, the effects of ALDH2 deficiency on mammary gland development and homeostasis without alcohol exposure remain unexplored. To investigate the effects of ALDH2 deficiency on mammary proliferation and development, we utilized a C57BL/6-based ALDH2 knockout (Aldh2−/−) mouse model. Our findings revealed that Aldh2−/− mice displayed hyperproliferative mammary glands with increased epithelial cell density, ductal expansion, and increased numbers of Ki67+ cells. Flow cytometry analysis revealed expansion of luminal and basal epithelial subpopulations, accompanied by enhanced mammary epithelial stemness, as indicated by increased mammosphere formation and colony-forming efficiency. At the molecular level, ALDH2 deficiency activated oxidative stress pathways, reflected by elevated 8-OHdG, p38 MAPK, NF-κB, and Nrf2 signaling, along with DNA damage responses involving p53 and H2A.X. We also identified a novel upregulation of RANK and RANKL in Aldh2−/− mammary glands, identifying the RANK/RANKL upregulation associated with NF-κB/p38 MAPK activation and enhanced mammary stemness. Furthermore, hormonal dysregulation was observed, with a significant increase in ERα and PR expression and phosphorylation. Dysregulated ER signaling correlated with enhanced erbB3 activation and downstream signaling, including the cyclin D1–pRb-E2F1 axis. These findings suggest that ALDH2 deficiency, possibly through accumulated endogenous aldehydes, profoundly alters mammary morphogenesis, epithelial repopulation, and stemness. These effects are associated with activation of oxidative stress and DNA damage pathways, together with upregulation of RANKL, estrogen receptor and receptor tyrosine kinase signaling. This study is the first to identify ALDH2 deficiency as a novel factor associated with mammary epithelial alterations that may create a tissue state that could predispose to oncogenic transformation. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Breast Cancer)

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19 pages, 1201 KB

Open AccessReview

The Role of cGAS-STING-Driven PANoptosis in Neurodegenerative Diseases and Therapeutic Prospects

by Xinyi Hou and Wei Yu

Cells 2026, 15(18), 1631; https://doi.org/10.3390/cells15181631 - 9 Sep 2026

Abstract

Neurodegenerative diseases share features of neuronal loss, neuroinflammation, and protein aggregation. The cGAS-STING pathway, a key DNA sensor, mediates neuroinflammation via TBK1-IRF3 and IKK-NF-κB axes, inducing type I interferons and pro-inflammatory cytokines. This pathway upregulates ZBP1, promotes PANoptosome assembly, and triggers PANoptosis, releasing [...] Read more.

Neurodegenerative diseases share features of neuronal loss, neuroinflammation, and protein aggregation. The cGAS-STING pathway, a key DNA sensor, mediates neuroinflammation via TBK1-IRF3 and IKK-NF-κB axes, inducing type I interferons and pro-inflammatory cytokines. This pathway upregulates ZBP1, promotes PANoptosome assembly, and triggers PANoptosis, releasing DAMPs and creating a self-amplifying “inflammation–death” cycle. In Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis, pathological proteins (Aβ, Tau, α-synuclein, TDP-43) or genetic defects (e.g., C9orf72 repeats) cause mitochondrial DNA leakage or genomic instability, activating this axis. This review highlights the cGAS-STING-PANoptotic cascade as a shared pathogenic mechanism and discusses the current evidence and remaining challenges in confirming this hypothesis. Full article

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16 pages, 4312 KB

Open AccessArticle

In Vitro Glutamine Adaptability in Murine Liver- but Not Lung-Metastasizing Triple-Negative Breast Cancer Cells

by Marjorie Anne Layosa, Keigo Tomoo, Madeline P. Sheeley, Michael F. Coleman, Chaylen Andolino, Michael K. Wendt, Stephen D. Hursting and Dorothy Teegarden

Cells 2026, 15(18), 1630; https://doi.org/10.3390/cells15181630 - 9 Sep 2026

Abstract

Background: Metabolic adaptability plays a critical role in supporting the growth and survival of metastatic breast cancer cells, and potentially supports site-specific metastasis. This study investigates the differential metabolism of glutamine and adaptability to varying glutamine levels of triple-negative breast cancer (TNBC) cells [...] Read more.

Background: Metabolic adaptability plays a critical role in supporting the growth and survival of metastatic breast cancer cells, and potentially supports site-specific metastasis. This study investigates the differential metabolism of glutamine and adaptability to varying glutamine levels of triple-negative breast cancer (TNBC) cells that metastasize to the lungs (metM-Wnt^Lung) or liver (metM-Wnt^Liver). Methods: The metastatic cell lines were exposed to varying in vitro glutamine concentrations (0.5, 2, and 4 mM). Cell viability, migration, ¹⁴C-glutamine uptake, mRNA abundance of metabolic enzymes, and ¹³C₅-glutamine cellular flux, were measured. Results: At an intermediate level of in vitro glutamine supplementation (2 mM), metM-Wnt^Lung cells exhibited greater glutamine uptake, catabolic enzyme expression, and flux of glutamine-derived carbon into the TCA cycle compared with metM-Wnt^Liver cells. Despite this, metM-Wnt^Liver cells were more viable and migratory than metM-Wnt^Lung cells under both higher (4 mM) and lower (0.5 mM) glutamine levels, suggesting metabolic adaptability. Exposure to ammonia upregulated ammonia-assimilating enzymes in metM-Wnt^Liver, but not metM-Wnt^Lung cells, plausibly mitigating ammonia toxicity in higher glutamine conditions. In glutamine-deprived conditions, the metM-Wnt^Lung cells maintained higher glutamine oxidation, but the metM-Wnt^Liver cells had higher total glutathione and GSH/GSSG ratios and enhanced resistance to oxidative stress, suggesting glutamate utilization toward glutathione synthesis. Additionally, metM-Wnt^Liver cells utilized glucose-derived carbons through pyruvate carboxylase (PC) to maintain TCA cycle activity, with elevated PC expression and M+3-labeled oxaloacetate enrichment to a greater extent than metM-Wnt^Lung cells. PC silencing in metM-Wnt^Liver cells enhanced cell viability under glutamine deprivation, which was reversed by inhibiting phosphoglycerate dehydrogenase (PHGDH, a key enzyme in de novo serine synthesis). We propose that PC activity compensates for low glutamine levels, including diverting glucose to adaptive pathways such as de novo serine synthesis. Conclusions: Overall, our findings demonstrate that metM-Wnt^Liver cells, but not metM-Wnt^Lung cells, exhibit glutamine-specific metabolic plasticity, characterized by the modulation of glutamine catabolism, enhanced ammonia metabolism and antioxidant defense, and support of glucose metabolism, which are associated with better cell survival and migration under glutamine excess and deprivation. Full article

(This article belongs to the Special Issue Cellular Pathology: Emerging Discoveries and Perspectives in the USA)

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30 pages, 2926 KB

Open AccessReview

The Adaptive Cellular State Model: A Conceptual Framework Linking Dietary Quality to Exercise-Induced Cellular Adaptation

by Mario Muñoz-López, Gonzalo Quesada-Fernández, Edgar Simón Sancho-Haro, José Francisco López-Gil, Miguel López-Moreno and José Francisco Tornero-Aguilera

Cells 2026, 15(18), 1629; https://doi.org/10.3390/cells15181629 - 8 Sep 2026

Abstract

Exercise is a recurrent multidimensional perturbation that initiates biological adaptation, yet responses to comparable training programmes remain heterogeneous. This critical narrative Review introduces the Adaptive Cellular State (ACS) Model as a heuristic framework for examining how the biological context present before training may [...] Read more.

Exercise is a recurrent multidimensional perturbation that initiates biological adaptation, yet responses to comparable training programmes remain heterogeneous. This critical narrative Review introduces the Adaptive Cellular State (ACS) Model as a heuristic framework for examining how the biological context present before training may contribute to variation in the subsequent processing and consolidation of exercise-induced perturbations. ACS is defined as a pre-existing, dynamic and multidimensional biological configuration that may condition how exercise-induced perturbations are received, decoded, executed and retained across repeated adaptive cycles. The model organizes nine interacting domains—mitochondrial quality, metabolic flexibility, nutrient sensing, redox responsiveness, inflammatory tone, microbiota-derived signalling, endothelial function, proteostasis and epigenetic readiness—and proposes four emergent properties: gain, fidelity, biological noise and memory. These domains and properties are theoretical constructs rather than validated ACS measurements or clinical categories. Exercise remains the indispensable initiating stimulus, whereas nutrition may act through distinct routes: acute nutritional conditions may modify the internal perturbation generated during exercise, habitual dietary quality may influence selected components of the pre-existing biological context, and recovery nutrition may provide substrates or modify conditions relevant to remodelling. Nutrient-adequate dietary patterns emphasizing minimally processed foods and a diverse plant-food component represent plausible candidate exposures, but current evidence does not establish superiority over appropriately constructed high-quality omnivorous patterns or demonstrate greater long-term training adaptation. The ACS Model should therefore be interpreted as a prospective and falsifiable research framework whose validity depends on whether prespecified baseline ACS-related measures provide reproducible information about durable adaptation beyond conventional metabolic, fitness and training-history variables. Full article

(This article belongs to the Section Cellular Metabolism)

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28 pages, 14204 KB

Open AccessArticle

Bioactive Selenium Peptides Rescue Dopaminergic Neurodegeneration via Coordinated Signal Remodeling and Redox Reinforcement

by Xue Hou, Lin Luo, Ruojia Li, Yuying Li, Zhiyong Wang and Yangyang Wu

Cells 2026, 15(18), 1628; https://doi.org/10.3390/cells15181628 - 8 Sep 2026

Abstract

Selenium-dependent antioxidant systems are critical for neuronal redox balance, but whether Parkinson’s disease (PD) involves systemic selenium deficiency or selective utilization impairment remains unclear. Using Parkinson’s Progression Markers Initiative (PPMI) proteomic data, we identified specific downregulation of glutathione peroxidase 3 (GPX3) in cerebrospinal [...] Read more.

Selenium-dependent antioxidant systems are critical for neuronal redox balance, but whether Parkinson’s disease (PD) involves systemic selenium deficiency or selective utilization impairment remains unclear. Using Parkinson’s Progression Markers Initiative (PPMI) proteomic data, we identified specific downregulation of glutathione peroxidase 3 (GPX3) in cerebrospinal fluid in PD, suggesting a compartment-specific alteration in GPX3-related antioxidant defense rather than a uniform systemic selenium deficit. Inorganic selenium sources suffer from low bioavailability and narrow therapeutic windows. We therefore developed a selenium-enriched peptide fraction (IPP-Se-F12) via controlled selenization of Idesia polycarpa Maxim. cake meal peptides, and characterized its selenium content, size distribution, and radical-scavenging activity. In SH-SY5Y and nematode models, IPP-Se-F12 attenuated 6-hydroxydopamine (6-OHDA)-induced cell death and rescued locomotor and dopamine-dependent behaviors more effectively than sodium selenite treatment. RNAseq further showed that IPP-Se-F12 treatment was associated with transcriptional changes in dephosphorylation, axon-guidance, and GPX3-centered antioxidant networks, including increased expression of gpx-3 and gpx-5. This study supports IPP-Se-F12 as a plant-derived selenium-associated peptide fraction with protective activity in cellular and nematode models and identifies GPX-related antioxidant regulation as a candidate mechanism for further investigation. Full article

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32 pages, 3802 KB

Open AccessReview

Multiple Mechanisms of Dopamine Modulation of Neuronal Excitability and Neurotransmission in the Striatum: A Personal and Historical Perspective

by Carlos Cepeda

Cells 2026, 15(18), 1627; https://doi.org/10.3390/cells15181627 - 8 Sep 2026

Abstract

3,4-dihydroxyphenethylamine, commonly known as dopamine (DA), is a neuromodulator that fine-tunes neuronal excitability, neurotransmitter release, and the effects of other neurotransmitters on postsynaptic neurons. DA, acting on D1 and D2 receptor families, is involved in myriad functions. In the striatum, it is mainly [...] Read more.

3,4-dihydroxyphenethylamine, commonly known as dopamine (DA), is a neuromodulator that fine-tunes neuronal excitability, neurotransmitter release, and the effects of other neurotransmitters on postsynaptic neurons. DA, acting on D1 and D2 receptor families, is involved in myriad functions. In the striatum, it is mainly implicated in motor control, motivation, and reward mechanisms. In the cerebral cortex it participates in attention processes, working memory, long-term memory, etc. DA overproduction or deficits lead to neuronal circuit imbalance that underlies a number of neurological and psychiatric diseases, including Parkinson’s disease (PD), schizophrenia, Huntington’s disease (HD), and substance use disorders (SUDs), to name a few. DA regulates neuronal excitability by modulating ion channels, the release of excitatory (glutamate) and inhibitory (γ-aminobutyric acid, GABA) neurotransmitters, and postsynaptic interactions with glutamate and GABA receptors. Together, these pre- and postsynaptic actions of DA underlie a number of synergistic or antagonistic actions that have important implications for setting membrane potentials, improving the signal-to-noise ratio, and directing the sign of synaptic plasticity. In this review, I will first provide a historical overview of the many studies exploring DA actions in the brain, with particular focus on the striatum. Then, I will emphasize some of the contributions of our laboratory to the understanding of DA modulatory effects from an electrophysiological perspective. Finally, I will discuss the mechanistic and therapeutic implications of DA function and dysfunction. Full article

(This article belongs to the Section Cellular Neuroscience)

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19 pages, 1580 KB

Open AccessReview

Current Perspectives on the Role of Collagen Peptide Fragments in Health and Disease

by Kenzi-Alayna Campbell, Sanjay P. Tirupattur, Gia Katwa and Laxmansa C. Katwa

Cells 2026, 15(18), 1626; https://doi.org/10.3390/cells15181626 - 8 Sep 2026

Abstract

Collagen is the most abundant protein in the human body and a vital component of the extracellular matrix (ECM), where it maintains structural architecture, strength, and mechanical stability throughout the body. Collagen undergoes continuous turnover and remodeling mediated by matrix metalloproteinases (MMPs) and [...] Read more.

Collagen is the most abundant protein in the human body and a vital component of the extracellular matrix (ECM), where it maintains structural architecture, strength, and mechanical stability throughout the body. Collagen undergoes continuous turnover and remodeling mediated by matrix metalloproteinases (MMPs) and other proteases to generate collagen peptide fragments (CPFs). CPFs were long considered inert byproducts of collagen turnover but are now recognized to have two overlapping roles: as circulating and urinary biomarkers of ECM remodeling, and as beneficial or adverse bioactive matrikines that directly regulate inflammation, angiogenesis, fibrosis, immune responses, and tissue remodeling. This review focuses on current evidence regarding the biological activities of various CPFs across cardiovascular, cancer, and pulmonary systems. We conclude by discussing various perspectives, including clinical and therapeutic applications and future directions. Full article

(This article belongs to the Special Issue Protein and RNA Regulation in Cells)

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13 pages, 5388 KB

Open AccessArticle

Smooth Muscle Cell MAPK14 Promotes Vascular Calcification During Hyperlipidemic Aging

by Nestor Ishimwe, Yuchi Tu, Chunhui Wang, W. Bart Bryant, Wei Zhang, Yabing Chen and Xiaochun Long

Cells 2026, 15(18), 1625; https://doi.org/10.3390/cells15181625 - 8 Sep 2026

Abstract

Vascular calcification is a hallmark of vascular aging that is accelerated by hyperlipidemia and contributes to adverse cardiovascular outcomes. Although vascular smooth muscle cells (VSMCs) are key mediators of vascular calcification, the signaling pathways linking aging-associated stress to osteogenic remodeling remain incompletely understood. [...] Read more.

Vascular calcification is a hallmark of vascular aging that is accelerated by hyperlipidemia and contributes to adverse cardiovascular outcomes. Although vascular smooth muscle cells (VSMCs) are key mediators of vascular calcification, the signaling pathways linking aging-associated stress to osteogenic remodeling remain incompletely understood. To define the role of MAPK14 (p38α) in vascular aging, we integrated bulk RNA sequencing of young and aged mouse aortas with published single-nucleus RNA sequencing data from VSMC-specific Mapk14 knockout (KO) mice. Bulk RNA-seq identified age-associated activation of extracellular matrix remodeling, calcification, inflammatory, and senescence-associated gene programs, accompanied by increased p38 MAPK signaling. Single-nucleus RNA-seq further demonstrated that Mapk14 KO attenuated proliferative, inflammatory, fibrotic, and ossification-associated gene modules in VSMCs. Consistent with these transcriptomic findings, RUNX2 expression was markedly increased in aged aortas, whereas aged Mapk14 KO mice exhibited reduced RUNX2 expression together with attenuated vascular calcification, fibrosis, and inflammatory cell infiltration compared with wild-type controls. Collectively, these results identify VSMC MAPK14 as an important regulator of vascular calcification during hyperlipidemic aging and demonstrate that MAPK14 deficiency is associated with reduced RUNX2 expression and attenuated fibro-inflammatory vascular remodeling. These findings support MAPK14 as a potential therapeutic target for limiting vascular calcification and associated pathological remodeling during aging. Full article

(This article belongs to the Section Cellular Aging)

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