Cells

15 pages, 671 KB

Open AccessReview

Cellular Interactions of Cardiac Repair After Myocardial Infarction

by Merry L. Lindsey, Ashton F. Oliver, Amadou Gaye, Pius N. Nde, Kristine Y. DeLeon-Pennell and Germán E. González

Cells 2025, 14(23), 1903; https://doi.org/10.3390/cells14231903 (registering DOI) - 1 Dec 2025

Abstract

When blood flow to a part of the myocardial muscle is reduced or blocked, it leads to tissue ischemia in that region. Myocardial infarction (MI) occurs when the ischemic insult is of sufficient duration in time to induce cardiomyocyte death and subsequent activation [...] Read more.

When blood flow to a part of the myocardial muscle is reduced or blocked, it leads to tissue ischemia in that region. Myocardial infarction (MI) occurs when the ischemic insult is of sufficient duration in time to induce cardiomyocyte death and subsequent activation of the innate immune response. MI initiates a complex cascade of cellular and molecular events within the left ventricle. Inflammatory cells rapidly infiltrate the infarcted area to remove necrotic tissue, setting the stage for reparative wound healing processes. Over the ensuing days, various cell populations—including leukocytes, fibroblasts, and endothelial cells—are attracted to the infarcted site by inflammatory cytokines and chemokines. The activated cells at the site of injury contribute to tissue remodeling and scar formation through the deposition of extracellular matrix components, particularly collagen. While scar formation is essential for structural stabilization of the infarct region to replace the loss of cardiomyocytes, scar tissue also increases myocardial stiffness and impairs cardiac contractile function. This review summarizes our knowledge regarding cellular dynamics, inflammatory signaling, and cardiac remodeling that govern MI healing. We identify the current gaps in the field and provide a foundational resource for those seeking to understand the biological underpinnings of cardiac repair following MI. Full article

(This article belongs to the Special Issue The Roles of the Extracellular Matrix in Cardiac Structure and Function: A Commemorative Issue in Honor of Dr. Thomas K. Borg)

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32 pages, 6169 KB

Open AccessFeature PaperReview

Toll-like Receptors in Inborn Errors of Immunity in Children: Diagnostic Potential and Therapeutic Frontiers—A Review of the Latest Data

by Aleksandra Jurczuk, Paulina Bałdyga, Adam Płoński, Maria Jurczuk and Marzena Garley

Cells 2025, 14(23), 1902; https://doi.org/10.3390/cells14231902 (registering DOI) - 1 Dec 2025

Abstract

Inborn errors of immunity (IEIs), formerly referred to as primary immunodeficiencies (PID), represent a heterogeneous group of hereditary disorders that significantly increase patients’ susceptibility to severe and recurrent infections. Toll-like receptors (TLRs) play a pivotal role in host defense as fundamental components of [...] Read more.

Inborn errors of immunity (IEIs), formerly referred to as primary immunodeficiencies (PID), represent a heterogeneous group of hereditary disorders that significantly increase patients’ susceptibility to severe and recurrent infections. Toll-like receptors (TLRs) play a pivotal role in host defense as fundamental components of innate immunity, while also linking it to adaptive immune responses. This review summarizes advances in understanding the involvement of TLRs in the pathogenesis of IEIs in children. It highlights genetic defects such as deficiencies in MyD88, IRAK-4, NEMO, and TLR3, which lead to distinct clinical phenotypes, for example, increased susceptibility to bacterial infections or herpes simplex virus type-1 (HSV-1) encephalitis. The review also examines more complex disorders, including chronic granulomatous disease (CGD), common variable immunodeficiency (CVID), and X-linked agammaglobulinemia (XLA), in which TLR signaling may be either impaired or dysregulated. This analysis demonstrates the growing importance of functional assays evaluating TLR activity as a diagnostic tool complementary to genetic testing, as well as their potential to precisely characterize immunological phenotypes. Furthermore, current therapeutic perspectives are discussed, including the use of TLR agonists, which have shown promising results in oncology, the role of gene therapy as a causal treatment option, and a proposed diagnostic algorithm incorporating TLR-based evaluation. Despite significant progress, substantial knowledge gaps remain, particularly regarding the full spectrum of TLR signaling abnormalities across IEI subtypes. The conclusions emphasize the need for large-scale, international studies to achieve a comprehensive understanding of pathogenic mechanisms and to develop more targeted and effective therapeutic interventions for children affected by these rare disorders. Full article

(This article belongs to the Collection Toll-Like Receptors in Pathologies)

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24 pages, 3220 KB

Open AccessArticle

Interplay Between Ribosomal Gene Deficiency and Calorie Restriction in Shaping Yeast Biosynthetic Capacity

by Roman Maslanka and Renata Zadrag-Tecza

Cells 2025, 14(23), 1901; https://doi.org/10.3390/cells14231901 (registering DOI) - 1 Dec 2025

Abstract

Biosynthetic capacity, particularly in protein production, significantly influences cells’ physiological efficiency and their ability to proliferate. Numerous studies have suggested that reducing protein synthesis can extend lifespan and improve indicators of cellular efficiency. However, the precise mechanism behind this phenomenon remains unclear. This [...] Read more.

Biosynthetic capacity, particularly in protein production, significantly influences cells’ physiological efficiency and their ability to proliferate. Numerous studies have suggested that reducing protein synthesis can extend lifespan and improve indicators of cellular efficiency. However, the precise mechanism behind this phenomenon remains unclear. This study employed a model combining two methods to reduce biosynthetic activity—the deletion of genes encoding ribosomal proteins (e.g., RPL20A, RPL20B, and RPS6B) and calorie restriction—to analyse the relationships among biosynthetic capacity, cell size, and physiological efficiency. The results indicate that, under calorie restriction, parameters such as growth rate, cell size, protein content, metabolic activity, and glucose utilisation decrease significantly only in the wild-type strain. Conversely, yeast strains with deleted ribosomal protein genes—particularly Δrpl20a, which has the lowest biosynthetic capacity—exhibit a marked reduction in biosynthetic capacity under optimal conditions and no additional limiting effect from calorie restriction. These findings suggest the existence of a minimal threshold of biosynthetic capacity required to maintain a cell’s physiological efficiency. Thus, factors that reduce biosynthetic efficiency only have a noticeable effect on cells with biosynthetic activity levels above the minimal threshold. Full article

(This article belongs to the Special Issue Functional Genomics and Morphological Profiling in Saccharomyces cerevisiae)

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27 pages, 2523 KB

Open AccessReview

Shaping the Immune Response: Cathepsins in Virus-Dendritic Cell Interactions

by Adrianna Niedzielska, Magdalena Bossowska-Nowicka, Zuzanna Biernacka, Karolina Gregorczyk-Zboroch, Felix N. Toka and Lidia Szulc-Dąbrowska

Cells 2025, 14(23), 1900; https://doi.org/10.3390/cells14231900 (registering DOI) - 1 Dec 2025

Abstract

Dendritic cells (DCs) are among the first immune cells to detect viral invasion and play a central role in initiating and shaping antiviral immune responses. Many innate and adaptive immune functions of DCs are regulated by cathepsins, proteolytic enzymes primarily found in acidic [...] Read more.

Dendritic cells (DCs) are among the first immune cells to detect viral invasion and play a central role in initiating and shaping antiviral immune responses. Many innate and adaptive immune functions of DCs are regulated by cathepsins, proteolytic enzymes primarily found in acidic endolysosomal compartments. Different DC subsets exhibit distinct cathepsin expression patterns, influencing their functional capacities and interactions with viruses. In DCs, cathepsins contribute to virus sensing through innate receptors, regulate cytokine production and DC migration, and are essential for viral antigen degradation and loading onto MHC molecules for T-cell activation. Many viruses, however, have evolved mechanisms to alter cathepsin expression and activity, thereby subverting DC function and promoting their own persistence. Indeed, cathepsins can facilitate viral entry into DCs, promote viral replication, and support immune evasion strategies. In this review, we summarize recent advances in understanding the role of cathepsins in DC–virus interactions, emphasizing both how DCs exploit cathepsins to generate protective immune responses and how viruses manipulate cathepsin activity to their advantage. We particularly focus on clinically relevant viral pathogens, including HIV, influenza virus, hepatitis C virus, human cytomegalovirus, Ebola virus, and SARS-CoV-2, to illustrate the multifaceted influence of cathepsins on DC biology during viral infection. Full article

(This article belongs to the Special Issue The Cellular and Molecular Mechanisms of Immunity to Infectious Viruses)

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21 pages, 609 KB

Open AccessReview

Conservative Management of Focal Chondral Lesions of the Knee and Ankle: Current Concepts

by Filippo Migliorini, Raju Vaishya, Julian Koettnitz, Madhan Jeyaraman, Luise Schäfer, Jörg Eschweiler and Francesco Simeone

Cells 2025, 14(23), 1899; https://doi.org/10.3390/cells14231899 (registering DOI) - 1 Dec 2025

Abstract

Focal chondral defects of the knee and ankle remain a challenging clinical condition, particularly in young and active patients, as they often cause pain, mechanical symptoms, and functional limitation without necessarily progressing to osteoarthritis (OA). This narrative review summarises current evidence on non-operative [...] Read more.

Focal chondral defects of the knee and ankle remain a challenging clinical condition, particularly in young and active patients, as they often cause pain, mechanical symptoms, and functional limitation without necessarily progressing to osteoarthritis (OA). This narrative review summarises current evidence on non-operative strategies for managing focal chondral lesions in non-arthritic joints, emphasising the role of rehabilitation as the central component of care. A thematic literature search was conducted across major databases for studies published between 2000 and 2025, selecting articles based on clinical relevance. Structured rehabilitation programmes based on load optimisation, neuromuscular retraining, and progressive strengthening represent the foundation of conservative management. Pharmacological agents and intra-articular injectables may provide temporary relief, although the evidence supporting their efficacy remains heterogeneous and primarily short-term. Nutraceuticals and physical modalities show encouraging but inconsistent results, limited by methodological variability and undefined dosing. Overall, conservative treatment should be tailored to the individual patient’s biomechanical and biological profile, integrating rehabilitation with selected adjuncts when appropriate. Future research should focus on developing standardised rehabilitation protocols, identifying predictors of recovery, and clarifying the biological mechanisms that sustain symptom improvement in focal cartilage pathology. Full article

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22 pages, 2846 KB

Open AccessReview

From Cells to Organoids: Approaches, Regulatory Mechanisms, Applications, and Challenges of Organoids

by Lihong Wang, Anqi Chen, Dong Zhang and Zuping He

Cells 2025, 14(23), 1898; https://doi.org/10.3390/cells14231898 (registering DOI) - 29 Nov 2025

Abstract

Organoids refer to three-dimensional (3D) multicellular tissues derived from stem cells or single cells through their self-assembly capacity, and significantly, they mimic structural and functional characteristics of the organ from which they are derived. Organoids can maintain the gene expression profiles and mutational [...] Read more.

Organoids refer to three-dimensional (3D) multicellular tissues derived from stem cells or single cells through their self-assembly capacity, and significantly, they mimic structural and functional characteristics of the organ from which they are derived. Organoids can maintain the gene expression profiles and mutational features of parental cells during long-term culture. This makes organoids more relevant to the human bodies than gene knockout or overexpression animal models. Consequently, organoids have been widely used in various kinds of fields, including studies on organ developmental mechanisms, regenerative medicine, organ repair, the construction of disease models, high-throughput drug screening, and personalized medicine. Notably, significant progress has recently been made in organoid construction methodologies and regulatory mechanisms. These include the selections of starting cell sources, optimizing matrix materials, and the related cell signaling pathways. The rapid development of organoid technologies has provided new opportunities for their applications in organ transplantation, drug and toxicity screening, and molecular mechanisms for cell and tissue development. In this review, we discuss organoid construction methods involving the starting cell selection and spatiotemporal mediation, regulatory mechanisms with signaling molecules and pathways, and their applications in unveiling organogenesis mechanisms and disease etiology, drug screening, toxicity testing, personalized medicine, regenerative medicine, and alternatives to animal experiments. We also address the perspectives and challenges in this field with an aim to promote the development of organoids in basic research and translational medicine. Full article

(This article belongs to the Special Issue Organ Regeneration: Cells, Organoids and Organs)

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23 pages, 681 KB

Open AccessReview

Heat Shock Proteins in Head and Neck Squamous Cell Carcinoma

by Piotr Cierpikowski and Julia Bar

Cells 2025, 14(23), 1897; https://doi.org/10.3390/cells14231897 (registering DOI) - 28 Nov 2025

Abstract

Heat shock proteins (HSPs) are produced in response to stressful conditions, such as temperature, inflammation, infection, or exposure to environmental factors. HSPs are overexpressed in some malignancies, where they modulate the tumor microenvironment and influence cancer cell behavior and survival. Clinical trials for [...] Read more.

Heat shock proteins (HSPs) are produced in response to stressful conditions, such as temperature, inflammation, infection, or exposure to environmental factors. HSPs are overexpressed in some malignancies, where they modulate the tumor microenvironment and influence cancer cell behavior and survival. Clinical trials for breast, prostate, colon, and lung cancers exist, but not for head and neck squamous cell carcinomas (HNSCCs). Nonetheless, clinical studies on HSPs in HNSCC are still lacking. We review the role of HSPs with regard to physiology and as potential targets for molecular therapy in HNSCC. Full article

(This article belongs to the Special Issue New Trends and Advances in Diagnosis and Prognosis of Head and Neck Cancer from Carcinogenesis to Future Molecular Targeted Therapies: 2nd Edition)

21 pages, 643 KB

Open AccessReview

MicroRNA-221: A Context-Dependent Mediator in Human Diseases—Highlights from Molecular Mechanisms to Clinical Translation

by Qiu-Xiao Ren, Qian Zhao, Na Wu, Wanying Du, Zhaoyue Liu, Weiping J. Zhang and An-Jing Ren

Cells 2025, 14(23), 1896; https://doi.org/10.3390/cells14231896 (registering DOI) - 28 Nov 2025

Abstract

MicroRNA-221 (miR-221), a conserved small non-coding RNA, acts as a pivotal modulator of biological processes across multiple organ systems, the dysregulation of which is closely linked to the pathogenesis of various human diseases. This review systematically summarizes its multifaceted roles in cancer, cardiovascular [...] Read more.

MicroRNA-221 (miR-221), a conserved small non-coding RNA, acts as a pivotal modulator of biological processes across multiple organ systems, the dysregulation of which is closely linked to the pathogenesis of various human diseases. This review systematically summarizes its multifaceted roles in cancer, cardiovascular diseases (CVDs), neurological disorders, digestive system diseases, respiratory conditions, and adipose-endocrine dysfunction. In cancer, miR-221 exerts context-dependent oncogenic/tumor-suppressive effects by targeting phosphatase and tensin homolog (PTEN), cyclin-dependent kinase inhibitor 1c (CDKN1C/p57), and BCL2 modifying factor (Bmf), thereby regulating cell proliferation, invasion, stemness, and resistance to cancer therapy; it also serves as a non-invasive biomarker for glioma, papillary thyroid carcinoma, and colorectal cancer. In the cardiovascular system, it balances antiviral defense in viral myocarditis, modulates ventricular fibrotic remodeling in heart failure, and regulates endothelial function in atherosclerosis, with cell-type/ventricle-specific effects. In neurological disorders, it protects dopaminergic neurons in Parkinson’s disease and modulates microglial activation in epilepsy. It also regulates hepatic pathogen defense and intestinal mucosal immunity. Mechanistically, miR-221 alters cellular phenotypes by targeting tumor suppressors or signaling components (e.g., PI3K/AKT, TGF-β/suppressor of mothers against decapentaplegic homolog(SMAD), Wnt/β-catenin). Therapeutically, miR-221-targeting strategies show preclinical promise in cancer and CVDs. Despite this progress, further studies are needed to resolve context-dependent functional discrepancies, validate biomarker utility, and develop cell-specific delivery systems. This review provides a framework to understand its pathophysiologcial roles and potential application as a biomarker and therapeutic target. Full article

(This article belongs to the Special Issue The Silent Regulators: Non-Coding RNAs in Cell Function and Disease)

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43 pages, 544 KB

Open AccessReview

The Interplay Between Esophageal Adenocarcinoma and Its Tumor Microenvironment: Toward Innovative Therapies

by Rodanthi Fioretzaki, Eleni-Myrto Trifylli, Panagiotis Sarantis, Nikolaos Charalampakis, Konstantinos Christofidis, Markos Despotidis, Michalis V. Karamouzis, Stratigoula Sakellariou and Dimitrios Schizas

Cells 2025, 14(23), 1895; https://doi.org/10.3390/cells14231895 (registering DOI) - 28 Nov 2025

Abstract

Esophageal cancer (EC) is a highly aggressive gastrointestinal malignancy, with a notable increase in incidence over recent decades, representing a significant global health burden. The main histological subtypes are esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), with the former being closely [...] Read more.

Esophageal cancer (EC) is a highly aggressive gastrointestinal malignancy, with a notable increase in incidence over recent decades, representing a significant global health burden. The main histological subtypes are esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), with the former being closely associated with gastroesophageal reflux disease, Barrett’s esophagus, and obesity, and its incidence continues to increase in Western populations. The rising incidence of EC, combined with poor survival rates, underscores the need for new therapeutic approaches. A deeper understanding of the molecular basis of this prevalent malignancy may open new avenues for optimal therapeutic strategies, with immunotherapy now central in several clinical trials. Understanding the interplay between the tumor microenvironment (TME) and disease progression is pivotal for managing this malignancy, which remains highly challenging. This review highlights the role of the TME in EAC progression and drug resistance, and recent therapeutic advances. Full article

4 pages, 187 KB

Open AccessEditorial

Closing Editorial: Immunopathogenesis of Bacterial Infection

by Sasha Shafikhani

Cells 2025, 14(23), 1894; https://doi.org/10.3390/cells14231894 - 28 Nov 2025

Abstract

Bacterial infections remain a persistent and evolving threat to human health worldwide [...] Full article

(This article belongs to the Special Issue Immunopathogenesis of Bacterial Infection)

18 pages, 3199 KB

Open AccessArticle

ST32da, a Novel Salvia miltiorrhiza-Derived ATF3 Inducer, Alleviates Obesity-Related Diabetic Nephropathy in Mouse Models

by Hsi-Hsien Chen, Tzu-Ling Tseng, Hsiao-Fen Li, Ya-Ting Hsieh, Tu Tuan Tran, Yueh-Lin Wu and Heng Lin

Cells 2025, 14(23), 1893; https://doi.org/10.3390/cells14231893 (registering DOI) - 28 Nov 2025

Abstract

It is necessary to find novel therapeutic strategies for obesity-related diabetic nephropathy (DN) that target both metabolic dysfunction and renal inflammation. ST32da derived from Salvia miltiorrhiza (a well-recognized Traditional Chinese Medicine) induces activating transcription factor 3 (ATF3), a negative regulator of inflammation and [...] Read more.

It is necessary to find novel therapeutic strategies for obesity-related diabetic nephropathy (DN) that target both metabolic dysfunction and renal inflammation. ST32da derived from Salvia miltiorrhiza (a well-recognized Traditional Chinese Medicine) induces activating transcription factor 3 (ATF3), a negative regulator of inflammation and metabolic stress. However, the effects of ST32da on obesity-related DN remain underexplored. We investigated the therapeutic potential of ST32da, a synthetic ATF3 inducer derived from Salvia miltiorrhiza, in mitigating obesity-related DN in both in vivo and in vitro models. The Nephroseq database analysis was performed to explore the relationship between Atf3 expression and DN progression. ST32da was administered to db/db knockout and DBA mice to establish obesity-related DN models, and a high-fat diet (HFD)-induced mouse model of obesity-related DN was used to investigate the effects of Atf3 knockout. Molecular and biochemical analyses were conducted in cultured mesangial cells to elucidate the underlying mechanisms. ATF3 deficiency worsened obesity-related DN, increasing glomerular fibrosis, mortality, and inflammation. ST32da restored ATF3 levels and reduced renal injury, glomerular expansion, and pro-inflammatory cytokine expression (e.g., IL-6, TGFβ, TNFα). ST32da-treated mice exhibited reduced hepatic lipid accumulation and improved serum lipid profiles. In mesangial cells, ST32da localized to the cytoplasm and increased ATF3 activity, which suppressed RARRES1 expression and cytokine signaling. Mechanistically, ATF3 interacted with HDAC2 to repress NF-κB—dependent inflammatory gene expression. The findings suggest ST32da is a promising therapeutic candidate for obesity-related DN and associated metabolic disturbances, acting through ATF3 induction to suppress renal inflammation, lipotoxicity, and fibrosis. Full article

(This article belongs to the Special Issue Diabetes-Induced Organ Damage: Cellular Mechanisms and Therapeutic Opportunities)

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18 pages, 2588 KB

Open AccessArticle

Role of the Ca²⁺-ATPase Pump (SERCA) in Capacitation and the Acrosome Reaction of Cryopreserved Bull Spermatozoa

by Maia A. Rodríguez, Alejandro Orlowski, Enrique L. Portiansky and Paola Ferrero

Cells 2025, 14(23), 1892; https://doi.org/10.3390/cells14231892 - 28 Nov 2025

Abstract

Cryopreservation of sperm is a resource used for artificial insemination. In the case of bovines, it ensures the reproduction of animals through cells from males with a highlighted genetic background. The fertilisation capacity of sperm cells is achieved after capacitation, a process that [...] Read more.

Cryopreservation of sperm is a resource used for artificial insemination. In the case of bovines, it ensures the reproduction of animals through cells from males with a highlighted genetic background. The fertilisation capacity of sperm cells is achieved after capacitation, a process that includes subcellular modifications that could be altered by cryopreservation. Intracellular calcium handling plays a crucial role in the development of capacitation, culminating in the acrosomal reaction. SERCA protein is responsible for calcium reuptake into the acrosome, which is one of the main calcium reservoirs of sperm cells. In this work, we studied the relationships between SERCA activity and sperm motility, capacitation progression, actin polymerisation, and intracellular calcium handling in cryopreserved bovine spermatozoa. Inhibition of SERCA activity reduced sperm motility and induced hyperactivation patterns. It also increased the proportion of cells with acrosomal reaction and earlier actin depolymerisation, an event necessary to induce the acrosomal reaction. All changes occurred in concordance with a significant increase in intracellular calcium concentration (Ca²⁺). Our findings suggest that a thapsigargin-sensitive Ca²⁺ pump consistent with SERCA activity remains responsive in cryopreserved spermatozoa from the bull studied, under specific cryopreservation and incubation conditions tested, and may contribute to Ca²⁺ handling, motility changes, and premature acrosomal exocytosis. Full article

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

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Graphical abstract

17 pages, 12009 KB

Open AccessArticle

Endometrial Stromal Cells from Endometriosis Patients Reflect Lesion-Type-Specific Heterogeneity

by Daniel Rodriguez Gutierrez, Marianne R. Spalinger, Alina Astourian, Olivera Evrova, Lucie Berclaz, Monique Hartmann, Ioannis Dedes, Patrick Imesch, Julian M. Metzler, Isabelle Witzel, Mohaned Shilaih, Valentina Vongrad and Brigitte Leeners

Cells 2025, 14(23), 1891; https://doi.org/10.3390/cells14231891 - 28 Nov 2025

Abstract

Endometriosis, a disease affecting about one out of ten women, is characterized by the growth of endometrial-like tissue outside the uterine cavity. There is significant disease heterogeneity, but the pathophysiological mechanisms underlying differences in clinical presentation are poorly understood. Here, we investigated endometrial [...] Read more.

Endometriosis, a disease affecting about one out of ten women, is characterized by the growth of endometrial-like tissue outside the uterine cavity. There is significant disease heterogeneity, but the pathophysiological mechanisms underlying differences in clinical presentation are poorly understood. Here, we investigated endometrial stromal cells (ESCs) from different types of endometrial lesions (endometrioma, superficial, and deep endometrial lesions), which revealed distinct differences in proliferation, migration, and contractility among different lesion types and when compared to ESC from normal (eutopic) endometrium. In particular, ESCs from endometriotic lesions showed reduced proliferation but increased migratory capacity, an effect most pronounced in endometrioma ESCs but also evident in ESCs from superficial and deep lesions. ESCs from superficial and deep lesions—but not those from endometrioma—showed increased contractility, a feature involved in tissue scarring and pain perception. Transcriptomics and proteomics revealed changes in genes and proteins involved in cell division, proliferation, extracellular matrix organization, and migration in endometriosis vs. healthy ESCs. Overall, our results demonstrate that stromal cells from different endometriotic lesions show distinct in vitro phenotypes that might explain differences in clinical presentation. Further, these cells represent an excellent in vitro model for studying patho-mechanisms involved in endometriosis heterogeneity. Full article

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17 pages, 610 KB

Open AccessReview

Three-Dimensional Organization of Telomeres: An Emerging Prognostic Biomarker in Multiple Myeloma

by Yulia Shifrin and Sabine Mai

Cells 2025, 14(23), 1890; https://doi.org/10.3390/cells14231890 - 28 Nov 2025

Abstract

A crucial role of genome instability and telomeric dysfunction was demonstrated in multiple cancers, including multiple myeloma (MM). MM accounts for approximately 10% of all hematologic malignancies and includes asymptomatic pre-malignant monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Due [...] Read more.

A crucial role of genome instability and telomeric dysfunction was demonstrated in multiple cancers, including multiple myeloma (MM). MM accounts for approximately 10% of all hematologic malignancies and includes asymptomatic pre-malignant monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Due to the highly heterogeneous nature of the disease, there is an ongoing need for precise risk stratification and subsequent development of risk-adapted treatment strategies at every stage of disease and during disease progression. Telomere numbers, intensity, aggregates, and spatial arrangement within the nucleus were identified as prognostic biomarkers. Recent studies demonstrated that the three-dimensional (3D) analysis of key telomeric parameters is a reliable marker of the high risk of relapse in newly diagnosed MM (NDMM) patients and can predict the risk of progression of SMM patients. Telomeric parameters of malignant MM cells from the peripheral blood and bone marrow were similar, suggesting that 3D telomere profiling may assess MRD in liquid biopsies of MM patients. This review focuses on the prognostic value of 3D telomere profiling in MM. 3D spatial telomere analysis may potentially address a critical unmet clinical need in managing MM and, if incorporated into current guidelines, help to accurately predict disease status, progression risk, overall survival, and response to treatment. Full article

(This article belongs to the Special Issue Novel Insights into Molecular Mechanisms and Therapy of Myeloma)

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21 pages, 1395 KB

Open AccessReview

Dihydroorotate Dehydrogenase in Mitochondrial Ferroptosis and Cancer Therapy

by Jaewang Lee and Jong-Lyel Roh

Cells 2025, 14(23), 1889; https://doi.org/10.3390/cells14231889 - 28 Nov 2025

Abstract

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Since the identification of dihydroorotate dehydrogenase (DHODH) as a mitochondrial suppressor of ferroptosis in 2021, increasing evidence has highlighted its role in linking nucleotide metabolism, redox regulation, and tumor progression. [...] Read more.

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Since the identification of dihydroorotate dehydrogenase (DHODH) as a mitochondrial suppressor of ferroptosis in 2021, increasing evidence has highlighted its role in linking nucleotide metabolism, redox regulation, and tumor progression. We conducted a comprehensive review of publications on DHODH, ferroptosis, and cancer. Relevant studies were analyzed to synthesize mechanistic insights, translational implications, and therapeutic perspectives. DHODH, a flavin-dependent mitochondrial enzyme catalyzing the oxidation of dihydroorotate to orotate, integrates pyrimidine biosynthesis with electron transport chain activity. Beyond its canonical metabolic role, DHODH regenerates ubiquinol (CoQ₁₀H₂) to suppress mitochondrial lipid peroxidation and ferroptosis. Elevated DHODH expression in colorectal, hepatocellular, breast, renal, and brain cancers correlates with poor prognosis, therapy resistance, and immune evasion. Pharmacological inhibition of DHODH disrupts pyrimidine synthesis and redox defense, sensitizing GPX4-low tumors to ferroptosis. Preclinical studies demonstrate synergy between DHODH inhibitors and chemotherapy, radiotherapy, or immune checkpoint blockade. Nanoparticle-based delivery systems enhance therapeutic efficacy by simultaneously targeting multiple ferroptosis defense arms while reducing toxicity. DHODH serves as both a metabolic and redox checkpoint in cancer, linking ferroptosis suppression to proliferation and immune escape. Targeting DHODH offers a promising strategy to dismantle cancer resilience, particularly in combination with ferroptosis inducers and immunotherapies. Future research should focus on biomarker-guided stratification, nanomedicine platforms, and clinical translation of DHODH inhibitors. Full article

(This article belongs to the Special Issue New Advances in Anticancer Therapy)

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19 pages, 3635 KB

Open AccessArticle

Bletilla Striata Polysaccharide Alleviates Neutropenia by Promoting C/EBPε-Dependent Hematopoietic Reconstitution

by Yaru Cui, Yingying Luo, Cheng Zhang, Dan Shan, Yulin Feng, Shilin Yang, Lanying Chen and Jun Yu

Cells 2025, 14(23), 1888; https://doi.org/10.3390/cells14231888 - 28 Nov 2025

Abstract

Neutropenia is a common complication in oncology patients receiving chemotherapy, and rapid regeneration of functional neutrophils is critical for effective management. Bletilla striata polysaccharide (BSP) has shown therapeutic potential, but its mechanisms and molecular targets remain unclear. Here, we demonstrate that BSP accelerates [...] Read more.

Neutropenia is a common complication in oncology patients receiving chemotherapy, and rapid regeneration of functional neutrophils is critical for effective management. Bletilla striata polysaccharide (BSP) has shown therapeutic potential, but its mechanisms and molecular targets remain unclear. Here, we demonstrate that BSP accelerates the recovery of white blood cells, particularly neutrophils, in a chemotherapy-induced neutropenia (CIN) mouse model with cyclophosphamide (CY). The regenerated neutrophils retained phagocytic activity against bacteria, and BSP treatment significantly reduced mortality in the endotoxin-induced mouse death model. Furthermore, BSP enhanced the repopulation of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow and promoted cell-cycle entry, resulting in increased frequencies of long-term hematopoietic stem cells (LT-HSCs), multipotent progenitors 2 (MPP2), and MPP3/4 subsets. Both in vitro colony formation and in vivo competitive transplantation assays confirmed that BSP reshapes hematopoietic reconstitution and corrects aberrant myeloid differentiation. PCR array analysis of HSPCs indicated that this process is mediated by C/EBPε and its downstream genes (LTF, LCN2, and ELANE). Consistently, BSP failed to support myeloid reconstitution following C/EBPε knockdown in vitro. In a C/EBPε knockout mouse model, HSPCs repopulation and regeneration were impaired, and BSP failed to promote neutrophil recovery after CY challenge or the mobilization of MPP2 and MPP3/4 subsets. The regulatory effects of BSP on C/EBPε target genes were also abolished. In conclusion, our findings identify C/EBPε as a key mediator of BSP activity, driving HSPCs repopulation and restoring hematopoietic function. These results highlight BSP as a potential therapeutic strategy for chemotherapy-induced neutropenia. Full article

(This article belongs to the Special Issue Immunoregulatory Functions of Mesenchymal Stem Cells (MSCs))

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38 pages, 11833 KB

Open AccessArticle

Chronic Ethanol Exposure Induces Early Epithelial-to-Mesenchymal Transition (EMT) and Premalignant Changes in Gingival Keratinocytes: An In Vitro Model of Very Early Oral Carcinogenesis

by Martin Philipp Dieterle, Thorsten Steinberg, Ayman Husari and Pascal Tomakidi

Cells 2025, 14(23), 1887; https://doi.org/10.3390/cells14231887 - 27 Nov 2025

Abstract

Early molecular events underlying ethanol-induced oral squamous cell carcinoma development remain insufficiently understood, primarily due to a lack of suitable in vitro systems that recapitulate the initial stages of premalignant transformation. Therefore, a cell culture model of human gingival keratinocytes representing progressive stages [...] Read more.

Early molecular events underlying ethanol-induced oral squamous cell carcinoma development remain insufficiently understood, primarily due to a lack of suitable in vitro systems that recapitulate the initial stages of premalignant transformation. Therefore, a cell culture model of human gingival keratinocytes representing progressive stages of early ethanol-induced cell transformation was established and comprehensively characterized. The three cell lines, named “gingival keratinocytes” (GK), “epithelioid” (EPI) and “fibroblastoid” (FIB), and their derivatives were analyzed by morphological, cell biological and biochemical methods, with an emphasis on epithelial-to-mesenchymal transition (EMT)-related signaling pathways. All cell lines were non-tumorigenic in vitro. Chronic ethanol exposure induced distinct morphological and molecular alterations that capture early premalignant changes in vitro. This includes reduced E-Cadherin and enhanced Vimentin expression, accompanied by an increased production of reactive oxygen species. Notably, even morphologically stable cell lines displayed metabolic susceptibility to EMT induction, indicating the early activation of transformation-associated signaling cascades even in a premalignant state. These alterations, however, closely mirrored pathohistological features of oral squamous cell carcinomas such as loss of epithelial integrity and acquisition of mesenchymal characteristics. Collectively, the presented model provides a robust and accessible in vitro platform for investigating very early ethanol-induced oral carcinogenesis mechanisms that are relevant in a premalignant state and may facilitate the identification of diagnostic and preventive biomarkers to improve patient outcomes in alcohol-associated oral cancer and precursor lesions. Full article

(This article belongs to the Section Cellular Pathology)

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18 pages, 1382 KB

Open AccessReview

New Evidence in Male Infertility Diagnosis: The Role of Metabolomics

by Giuseppina Peluso, Marco Serrao, Lidia Urlandini, Vittoria Rago, Saveria Aquila and Adele Vivacqua

Cells 2025, 14(23), 1886; https://doi.org/10.3390/cells14231886 - 27 Nov 2025

Abstract

Male infertility affects a significant proportion of couples struggling to conceive and re-quire a comprehensive investigation into the underlying causes and potential diagnostic markers. Seminal biomarkers and multi-omic approaches, particularly metabolomics, have provided valuable insights into the alterations of molecular pathways associated with [...] Read more.

Male infertility affects a significant proportion of couples struggling to conceive and re-quire a comprehensive investigation into the underlying causes and potential diagnostic markers. Seminal biomarkers and multi-omic approaches, particularly metabolomics, have provided valuable insights into the alterations of molecular pathways associated with male infertility. This review systematically integrates literature, focusing on studies which examine the interaction between seminal biomarkers, metabolomics, and various omics technologies in the evaluation of sperm quality, and then male infertility. We high-light the importance of a multi-dimensional approach to decipher the complex etiology of male infertility and identify potential diagnostic markers. Full article

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28 pages, 586 KB

Open AccessReview

A New Look at the Role of Radiation-Related Epigenetic Mechanisms in Diagnosis and Anticancer Therapies

by Adam Jan Olichwier, Magdalena Bruzgo-Grzybko, Izabela Suwda Kalita, Natalia Bielicka, Ewa Chabielska and Anna Gromotowicz-Poplawska

Cells 2025, 14(23), 1885; https://doi.org/10.3390/cells14231885 - 27 Nov 2025

Abstract

Epigenetics encompasses heritable but reversible modifications of gene expression that occur without changes in the DNA sequence and involve mechanisms such as DNA and RNA methylation and histone modifications. These mechanisms modulate chromatin architecture, genome stability, and cellular responses to environmental stressors, and [...] Read more.

Epigenetics encompasses heritable but reversible modifications of gene expression that occur without changes in the DNA sequence and involve mechanisms such as DNA and RNA methylation and histone modifications. These mechanisms modulate chromatin architecture, genome stability, and cellular responses to environmental stressors, and their dysregulation contributes to oncogenesis and cancer progression. In parallel, radiotherapy remains a cornerstone of cancer treatment; furthermore, ionizing radiation induces epigenetic modifications alongside direct DNA double-strand breaks and oxidative damage. Radiation-induced epigenetic changes, including global or locus-specific DNA methylation shifts (e.g., genes promoter CpG islets), histone acetylation and methylation imbalances, are increasingly recognized as key contributors to molecular radioresistance. These adaptive responses may enhance tumor cell survival, affect therapeutic efficacy, and promote metastasis. Understanding the interplay between radiation exposure and epigenetic remodeling opens new perspectives for precision oncology and diagnostics. Epigenetic biomarkers hold potential for predicting treatment response and prognosis, while epigenetic modifiers may sensitize tumors to radiation. This review summarizes current evidence on radiation-induced epigenetic mechanisms and evaluates their diagnostic, prognostic, and therapeutic implications in cancer management. Full article

(This article belongs to the Topic Overview of Cancer Metabolism)

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Cells

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