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Cells
Volume 14
Issue 13
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Cells, Volume 14, Issue 13 (July-1 2025) – 99 articles

Cover Story (view full-size image): Liver fibrosis poses a major global health burden, highlighting the need for advanced in vitro liver models to study disease mechanisms and develop drug therapies. As hepatocyte-induced hepatic stellate cell (HSC) activation is one of the most important drivers of fibrosis development, the inclusion of these cell types in in vitro models is essential. While induced pluripotent stem cell (iPSC)-derived hepatocytes and HSCs provide patient-specific platforms, functional maturation is limited. Herein, we present liver organoids composed of iPSC‑derived hepatocytes and HSCs and demonstrate that activation of RXRA by its ligand 9‑cis‑retinoic acid improves hepatocyte metabolism, maintains HSC quiescence, and enhances response to fibrotic stimuli, offering a refined tool for modelling human liver fibrosis and drug-induced injury. View this paper
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18 pages, 2145 KiB  
Review
Expression of Aldehyde Dehydrogenase 1A1 in Relapse-Associated Cells in Acute Myeloid Leukemia
by Régis Costello, Garrett M. Dancik, Anaïs Dubiau, Lamia Madaci and Spiros Vlahopoulos
Cells 2025, 14(13), 1038; https://doi.org/10.3390/cells14131038 - 7 Jul 2025
Viewed by 93
Abstract
In acute myeloid leukemia (AML) it is important to elucidate the biological events that lead from remission to relapse, which have a high probability of leading to an adverse disease outcome. The cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1A1) is underexpressed in [...] Read more.
In acute myeloid leukemia (AML) it is important to elucidate the biological events that lead from remission to relapse, which have a high probability of leading to an adverse disease outcome. The cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1A1) is underexpressed in AML cells when compared to healthy cells, both at the RNA level and at the protein level, and at least in the former, both in the bone marrow and in peripheral blood. Nonetheless, ALDH1A1/ALDH1A2 activity increases in AML cells during disease relapse and is higher in adverse prognosis AML in comparison with favorable prognosis AML. Furthermore, especially in relapsed AML and in unfavorable AML, AML cells rich in ALDH1A1 can contain high levels of reactive oxygen species (ROS), in parallel with high ALDH1A1/2 activity. This metabolic feature is clearly incompatible with normal stem cells. The term “stem-like” therefore is useful to coin malignant cells with a variety of genetic makeups, metabolic programming and biomarkers that converge in the function of survival of clones sufficient to sustain, spread and re-establish neoplastic disease. Therefore, AML “stem-like” cells survive cancer treatment that eradicates other malignant cell clones. This fact differentiates AML “stem-like” cells from normal stem and progenitor cells that function in tissue regeneration as part of a distinct hierarchical order of cell phenotypes. The ODYSSEY clinical trial is a Phase I/II study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABD-3001, a novel therapeutic agent, in patients with AML who have relapsed or are refractory to standard treatments. In this context, ABD-3001 is used as an inhibitor of cytosolic ALDH1 enzymes, such as ALDH1A1 and ALDH1A2. Full article
(This article belongs to the Section Tissues and Organs)
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24 pages, 5625 KiB  
Article
Ultrastructural Changes of the Peri-Tumoral Collagen Fibers and Fibrils Array in Different Stages of Mammary Cancer Progression
by Marco Franchi, Valentina Masola, Maurizio Onisto, Leonardo Franchi, Sylvia Mangani, Vasiliki Zolota, Zoi Piperigkou and Nikos K. Karamanos
Cells 2025, 14(13), 1037; https://doi.org/10.3390/cells14131037 - 7 Jul 2025
Viewed by 266
Abstract
Breast cancer invasion and subsequent metastasis to distant tissues occur when cancer cells lose cell–cell contact, develop a migrating phenotype, and invade the basement membrane (BM) and the extracellular matrix (ECM) to penetrate blood and lymphatic vessels. The identification of the mechanisms which [...] Read more.
Breast cancer invasion and subsequent metastasis to distant tissues occur when cancer cells lose cell–cell contact, develop a migrating phenotype, and invade the basement membrane (BM) and the extracellular matrix (ECM) to penetrate blood and lymphatic vessels. The identification of the mechanisms which induce the development from a ductal carcinoma in situ (DCIS) to a minimally invasive breast carcinoma (MIBC) is an emerging area of research in understanding tumor invasion and metastatic potential. To investigate the progression from DCIS to MIBC, we analyzed peritumoral collagen architecture using correlative scanning electron microscopy (SEM) on histological sections from human biopsies. In DCIS, the peritumoral collagen organizes into concentric lamellae (‘circular fibers’) parallel to the ducts. Within each lamella, type I collagen fibrils align in parallel, while neighboring lamellae show orthogonal fiber orientation. The concentric lamellar arrangement of collagen may physically constrain cancer cell migration, explaining the lack of visible tumor cell invasion into the peritumoral ECM in DCIS. A lamellar dissociation or the development of small inter fiber gaps allowed isolated breast cancer cell invasion and exosomes infiltration in the DCIS microenvironment. The radially arranged fibers observed in the peri-tumoral microenvironment of MIBC biopsies develop from a bending of the circular fibers of DCIS and drive a collective cancer cell invasion associated with an intense immune cell infiltrate. Type I collagen fibrils represent the peri-tumoral nano-environment which can play a mechanical role in regulating the development from DCIS to MIBC. Collectively, it is plausible to suggest that the ECM effectors implicated in breast cancer progression released by the interplay between cancer, stromal, and/or immune cells, and degrading inter fiber/fibril hydrophilic ECM components of the peritumoral ECM, may serve as key players in promoting the dissociation of the concentric collagen lamellae. Full article
(This article belongs to the Section Cell Microenvironment)
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23 pages, 5386 KiB  
Article
Structural and Functional Characterization of N-Glycanase-1 Pathogenic Variants
by Antje Banning, Lukas Hoeren, Isis Atallah, Ralph Orczyk, David Jacquier, Diana Ballhausen and Ritva Tikkanen
Cells 2025, 14(13), 1036; https://doi.org/10.3390/cells14131036 - 7 Jul 2025
Viewed by 82
Abstract
NGLY1 deficiency is a congenital disorder of deglycosylation, caused by pathogenic variants of the NGLY1 gene. It manifests as global developmental delay, hypo- or alacrima, hypotonia, and a primarily hyperkinetic movement disorder. The NGLY1 enzyme is involved in deglycosylation of misfolded N-glycosylated proteins [...] Read more.
NGLY1 deficiency is a congenital disorder of deglycosylation, caused by pathogenic variants of the NGLY1 gene. It manifests as global developmental delay, hypo- or alacrima, hypotonia, and a primarily hyperkinetic movement disorder. The NGLY1 enzyme is involved in deglycosylation of misfolded N-glycosylated proteins before their proteasomal degradation and in the activation of transcription factors that control the expression of proteasomal subunits. Here, we have characterized the pathogenic NGLY1 variants found in three Swiss NGLY deficiency patients, as well as the most common pathogenic NGLY1 variant, Arg401*, found in about 20% of patients. Our functional and structural assessments of these variants show that they cause a profound reduction in NGLY1 activity, severely reduced expression of NGLY1 protein, and misprocessing of the transcription factor NFE2L1. Furthermore, transcription of proteasomal subunits and NGLY1 mRNA splicing are impaired by some of these variants. Our in silico structural analysis shows that the Arg390Gln substitution results in destabilization of NGLY1 structure due to a loss of an ionic interaction network of Arg390 and potentially impairment of protein–protein interactions. Our results provide important information on the functional and structural effects of pathogenic NGLY1 variants and pave the way for structure-based development of personalized treatment options. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Lysosomal Storage Disorders)
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22 pages, 3155 KiB  
Article
Dissecting the Immunological Microenvironment of Glioma Based on IDH Status: Implications for Immunotherapy
by Miyu Kikuchi, Hirokazu Takami, Yukari Kobayashi, Koji Nagaoka, Yosuke Kitagawa, Masashi Nomura, Shunsaku Takayanagi, Shota Tanaka, Nobuhito Saito and Kazuhiro Kakimi
Cells 2025, 14(13), 1035; https://doi.org/10.3390/cells14131035 - 7 Jul 2025
Viewed by 63
Abstract
Gliomas, particularly IDH-wildtype ones, are associated with poor prognosis, yet their immunological landscape remains uncertain. We analyzed RNA sequencing data from 55 glioma patients, estimating immune infiltration with CIBERSORTx and immune cell states via Ecotyper. IDH-wildtype gliomas showed significantly higher immune cell infiltration [...] Read more.
Gliomas, particularly IDH-wildtype ones, are associated with poor prognosis, yet their immunological landscape remains uncertain. We analyzed RNA sequencing data from 55 glioma patients, estimating immune infiltration with CIBERSORTx and immune cell states via Ecotyper. IDH-wildtype gliomas showed significantly higher immune cell infiltration (p = 0.002), notably of regulatory T cells (Tregs) and macrophages, and a greater proportion of exhausted T cells compared to IDH-mutant gliomas. Clustering based on immune profiles revealed two groups. Cluster A, enriched for IDH-wildtype cases, exhibited heightened immune infiltration but also marked immunosuppression. Cluster B, which included both IDH-wildtype and mutant cases, showed lower levels of immune infiltration. Tumor-infiltrating lymphocyte (TIL) cultured from IDH-wildtype tumors demonstrated limited expansion following anti-PD-1, a CSF1R inhibitor, or a STAT3 inhibitor treatment, without clear cluster-specific differences. Tumor-reactive TILs were mainly observed in cluster A. These findings highlight that IDH-wildtype gliomas have an immunosuppressive and heterogeneous microenvironment, potentially limiting responses to single-agent immunotherapies. A personalized, multi-targeted approach addressing multiple immunosuppressive mechanisms may be essential to improve immunotherapy outcomes in this aggressive glioma subgroup. Full article
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12 pages, 1464 KiB  
Communication
Role of Kindlin-2-Expressing Extracellular Vesicles in the Invasiveness of Triple Negative Breast Cancer Tumor Cells
by Neelum Aziz Yousafzai, Mark F. Santos, Yeaji Kim, Nofar Avihen Schahaf, Kim Zielke, Lucia Languino, Khalid Sossey-Alaoui and Aurelio Lorico
Cells 2025, 14(13), 1034; https://doi.org/10.3390/cells14131034 - 7 Jul 2025
Viewed by 148
Abstract
Metastatic breast cancer (BC) is a major cause of cancer-related deaths among women. Its progression is influenced by extracellular vesicles (EVs) released by BC cells, which modulate distant tissue environments to promote metastasis. We previously identified the oncogenic protein Kindlin-2 (K2) as a [...] Read more.
Metastatic breast cancer (BC) is a major cause of cancer-related deaths among women. Its progression is influenced by extracellular vesicles (EVs) released by BC cells, which modulate distant tissue environments to promote metastasis. We previously identified the oncogenic protein Kindlin-2 (K2) as a key driver of BC metastasis, including its role in the nucleus in regulating cell senescence. Here, we investigated whether K2-containing EVs facilitate both autologous (cancer-to-cancer) and heterologous (cancer-to-stroma) communication to promote metastasis. We found that 10–15% of EVs from metastatic BC cells contained K2, while this subpopulation was nearly absent in the EVs from K2-knockout (KO) cells, indicating selective packaging. These EVs transferred K2 to recipient K2-KO cells, where they accumulated in the nucleus. Using a 3D tumorsphere assay, we showed that K2+ EVs enhanced cancer cell invasiveness. Moreover, K2+ EVs activated fibroblasts into a cancer-associated phenotype, increasing α-SMA and FAP expression. Conditioned media from these activated fibroblasts further boosted cancer cell invasion. These results show that EV-associated K2 is actively transferred to recipient cells and regulates metastasis through nuclear signaling, suggesting K2+ EVs are critical mediators of BC progression and potential targets for therapy. Full article
(This article belongs to the Special Issue New Insight into Tumor–Tumor Microenvironment Crosstalk)
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23 pages, 2570 KiB  
Communication
Duchenne Muscular Dystrophy Patient iPSCs—Derived Skeletal Muscle Organoids Exhibit a Developmental Delay in Myogenic Progenitor Maturation
by Urs Kindler, Lampros Mavrommatis, Franziska Käppler, Dalya Gebrehiwet Hiluf, Stefanie Heilmann-Heimbach, Katrin Marcus, Thomas Günther Pomorski, Matthias Vorgerd, Beate Brand-Saberi and Holm Zaehres
Cells 2025, 14(13), 1033; https://doi.org/10.3390/cells14131033 - 7 Jul 2025
Viewed by 85
Abstract
Background: Duchenne muscular dystrophy (DMD), which affects 1 in 3500 to 5000 newborn boys worldwide, is characterized by progressive skeletal muscle weakness and degeneration. The reduced muscle regeneration capacity presented by patients is associated with increased fibrosis. Satellite cells (SCs) are skeletal muscle [...] Read more.
Background: Duchenne muscular dystrophy (DMD), which affects 1 in 3500 to 5000 newborn boys worldwide, is characterized by progressive skeletal muscle weakness and degeneration. The reduced muscle regeneration capacity presented by patients is associated with increased fibrosis. Satellite cells (SCs) are skeletal muscle stem cells that play an important role in adult muscle maintenance and regeneration. The absence or mutation of dystrophin in DMD is hypothesized to impair SC asymmetric division, leading to cell cycle arrest. Methods: To overcome the limited availability of biopsies from DMD patients, we used our 3D skeletal muscle organoid (SMO) system, which delivers a stable population of myogenic progenitors (MPs) in dormant, activated, and committed stages, to perform SMO cultures using three DMD patient-derived iPSC lines. Results: The results of scRNA-seq analysis of three DMD SMO cultures versus two healthy, non-isogenic, SMO cultures indicate reduced MP populations with constant activation and differentiation, trending toward embryonic and immature myotubes. Mapping our data onto the human myogenic reference atlas, together with primary SC scRNA-seq data, indicated a more immature developmental stage of DMD organoid-derived MPs. DMD fibro-adipogenic progenitors (FAPs) appear to be activated in SMOs. Conclusions: Our organoid system provides a promising model for studying muscular dystrophies in vitro, especially in the case of early developmental onset, and a methodology for overcoming the bottleneck of limited patient material for skeletal muscle disease modeling. Full article
(This article belongs to the Special Issue The Current Applications and Potential of Stem Cell-Derived Organoids)
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26 pages, 1852 KiB  
Review
GIGYF2: A Multifunctional Regulator at the Crossroads of Gene Expression, mRNA Surveillance, and Human Disease
by Chen-Shuo Zhao, Shu-Han Liu, Zheng-Yang Li, Jia-Yue Chen and Xiang-Yang Xiong
Cells 2025, 14(13), 1032; https://doi.org/10.3390/cells14131032 - 5 Jul 2025
Viewed by 265
Abstract
GIGYF2 (Grb10-interacting GYF protein 2) functions as a versatile adaptor protein that regulates gene expression at various levels. At the transcriptional level, GIGYF2 facilitates VCP/p97-mediated extraction of ubiquitylated Rpb1 from stalled RNA polymerase II complexes during DNA damage response. In mRNA surveillance, GIGYF2 [...] Read more.
GIGYF2 (Grb10-interacting GYF protein 2) functions as a versatile adaptor protein that regulates gene expression at various levels. At the transcriptional level, GIGYF2 facilitates VCP/p97-mediated extraction of ubiquitylated Rpb1 from stalled RNA polymerase II complexes during DNA damage response. In mRNA surveillance, GIGYF2 participates in ribosome collision-induced quality control, nonsense-mediated decay, no-go decay, and non-stop decay pathways. Furthermore, GIGYF2 interacts with key factors including 4EHP, TTP, CCR4-NOT, DDX6, ZNF598, and TNRC6A to mediate translational repression and mRNA degradation. Additionally, dysregulation of GIGYF2 has been implicated in various pathological conditions, including metabolic diseases, vascular aging, viral infections, and neurodegenerative disorders. This review summarizes the structural and functional characteristics of GIGYF2, highlighting its importance in transcriptional regulation, mRNA surveillance, translational inhibition, and mRNA degradation, while also elucidating its potential as a therapeutic target for disease treatment. Full article
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16 pages, 2958 KiB  
Article
MK2 Inhibition as a Novel Treatment for Fibrosis in Primary Sclerosing Cholangitis via an IL-22-Dependent Mechanism
by Cody S. Howe and Ellen J. Beswick
Cells 2025, 14(13), 1031; https://doi.org/10.3390/cells14131031 - 5 Jul 2025
Viewed by 155
Abstract
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by bile duct inflammation and fibrosis, leading to cirrhosis and liver failure. Current therapies are limited to symptom management, with no approved treatments targeting fibrosis. We have identified the MAP kinase-activated protein kinase [...] Read more.
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by bile duct inflammation and fibrosis, leading to cirrhosis and liver failure. Current therapies are limited to symptom management, with no approved treatments targeting fibrosis. We have identified the MAP kinase-activated protein kinase 2 (MK2) pathway as a potential therapeutic target for treating PSC due to its role in promoting inflammatory cytokine production and activation of fibroblasts. Thus, MDR2 knockout mice were treated therapeutically with MK2 inhibitors, which led to significantly reduced hepatic inflammation and fibrosis. Liver enzymes, collagen 1A1, and fibronectin were decreased in serum with MK2 inhibitor treatment. Furthermore, the production of IL-6, TNFα, CXCL5, collagen 1A1, and fibronectin was decreased in liver tissues and liver stellate cells, whereas the production of IL-10, G-CSF, and IL-22 was increased. MDR2KO mice treated with IL-22 also showed improvements in inflammation and fibrosis, along with increased IL-10 and G-CSF production. Taken together, we identified both a direct mechanism of MK2 regulation of fibrotic factors and an indirect cytokine-mediated mechanism whereby the levels of IL-22, IL-10, and G-CSF were increased with MK2 inhibition and contributed to decreased levels of fibrotic factors. These data suggest that the MK2 pathway is a promising treatment target for PSC. Full article
(This article belongs to the Special Issue Fibrosis in Chronic Inflammatory Diseases)
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Graphical abstract

12 pages, 811 KiB  
Article
Kynurenic Acid Synthesis from D-Kynurenine in the Cerebellum: A Distinct Role of D-Amino Acid Oxidase
by Verónica Pérez de la Cruz, Korrapati V. Sathyasaikumar, Xiao-Dan Wang, Tonali Blanco Ayala, Sarah Beggiato, Dinora F. González Esquivel, Benjamin Pineda and Robert Schwarcz
Cells 2025, 14(13), 1030; https://doi.org/10.3390/cells14131030 - 5 Jul 2025
Viewed by 206
Abstract
The enzymatic formation of kynurenic acid (KYNA), a neuromodulator metabolite of the kynurenine pathway (KP) of tryptophan metabolism, in the mammalian brain is widely attributed to kynurenine aminotransferase II (KATII). However, an alternative biosynthetic route, involving the conversion of D-kynurenine (D-KYN) to KYNA [...] Read more.
The enzymatic formation of kynurenic acid (KYNA), a neuromodulator metabolite of the kynurenine pathway (KP) of tryptophan metabolism, in the mammalian brain is widely attributed to kynurenine aminotransferase II (KATII). However, an alternative biosynthetic route, involving the conversion of D-kynurenine (D-KYN) to KYNA by D-amino acid oxidase (D-AAO), may play a role as well. In the present study, we first confirmed that purified D-AAO efficiently converted D-KYN—but not L-KYN—to KYNA. We then examined KYNA formation from D-KYN (100 µM) in vitro, using tissue homogenates from several human brain regions. KYNA was generated in all areas, with D-AAO-specific production being most effective by far in the cerebellum. Next tested in homogenates from rat cerebellum, KYNA neosynthesis was significantly reduced by D-AAO inhibition, whereas KATII inhibition had no effect. Finally, KYNA production was assessed by in vivo microdialysis in rat cerebellum. Local D-KYN perfusion, alone and in combination with inhibitors of D-AAO (kojic acid) or aminotransferases (AOAA), caused a substantive increase in extracellular KYNA levels. This effect was attenuated dose-dependently by micromolar concentrations of kojic acid, whereas co-perfusion of AOAA (1 mM) was ineffective. Together, our findings indicate that D-AAO should be considered a major contributor to KYNA production in the cerebellum, highlighting region-specific qualitative differences in cerebral KYNA metabolism. Full article
(This article belongs to the Section Cell Signaling)
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38 pages, 4834 KiB  
Article
Neuro-Inflammatory and Behavioral Changes Are Selectively Reversed by Sceletium tortuosum (Zembrin®) and Mesembrine in Male Rats Subjected to Unpredictable Chronic Mild Stress
by Johané Gericke, Stephan F. Steyn, Francois P. Viljoen and Brian H. Harvey
Cells 2025, 14(13), 1029; https://doi.org/10.3390/cells14131029 - 4 Jul 2025
Viewed by 338
Abstract
Sceletium tortuosum (ST) induces antidepressant and anxiolytic effects, purportedly by monoamine regulation, anti-inflammatory and antioxidant properties, and phosphodiesterase 4 (PDE4) inhibition. These multimodal actions have not been demonstrated in an animal model of major depressive disorder. Wistar rats (both sexes) were subjected to [...] Read more.
Sceletium tortuosum (ST) induces antidepressant and anxiolytic effects, purportedly by monoamine regulation, anti-inflammatory and antioxidant properties, and phosphodiesterase 4 (PDE4) inhibition. These multimodal actions have not been demonstrated in an animal model of major depressive disorder. Wistar rats (both sexes) were subjected to 8-week unpredictable chronic mild stress, subsequently receiving saline, a standardized ST extract, Zembrin® 25 and 12.5 mg/kg (ZEM25 and ZEM12.5), its primary alkaloid mesembrine (MES), or escitalopram (20 mg/kg) for 36 days. Sucrose preference, open field, Barnes maze, and forced swim tests were performed, with cortico-hippocampal monoamines, inflammatory and oxidative stress markers analyzed post-mortem. Male, but not female rats, presented with increased anhedonia and anxiety but not despair. Males presented with increased hippocampal PDE4B expression, increased dopamine metabolites, and decreased cortical serotonin. In males, ZEM12.5 decreased anhedonia- and anxiety-like behavior, decreased cortical and hippocampal PDE4B, and increased plasma interleukin-10. MES induced a transient decrease in anhedonia-like behavior and increased hippocampal serotonergic and cortical dopaminergic activity, whilst decreasing hippocampal PDE4B. ZEM25 increased plasma interleukin-10 but decreased cortical glutathione, indicating paradoxical anti-inflammatory and prooxidant effects. ZEM12.5 and MES more effectively addressed anxious–depressive-like behavior and stress-induced inflammation and monoaminergic alterations, respectively. Multitargeted actions on monoamines, redox-inflammation, and PDE4 may provide ST with antidepressant effects across multiple symptom domains, although mutually synergistic/antagonistic effects of constituent alkaloids should be considered. Full article
(This article belongs to the Special Issue Neuroinflammation in Brain Health and Diseases)
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19 pages, 2479 KiB  
Article
Yoda1 Inhibits TGFβ-Induced Cardiac Fibroblast Activation via a BRD4-Dependent Pathway
by Perwez Alam, Sara M. Stiens, Hunter J. Bowles, Hieu Bui and Douglas K. Bowles
Cells 2025, 14(13), 1028; https://doi.org/10.3390/cells14131028 - 4 Jul 2025
Viewed by 159
Abstract
Fibrosis represents a pivotal pathological process in numerous diseases, characterized by excessive deposition of extracellular matrix (ECM) that disrupts normal tissue architecture and function. In the heart, cardiac fibrosis significantly impairs both structural integrity and functional capacity, contributing to the progression of heart [...] Read more.
Fibrosis represents a pivotal pathological process in numerous diseases, characterized by excessive deposition of extracellular matrix (ECM) that disrupts normal tissue architecture and function. In the heart, cardiac fibrosis significantly impairs both structural integrity and functional capacity, contributing to the progression of heart failure. Central to this process are cardiac fibroblasts (CFs), which, upon activation, differentiate into contractile myofibroblasts, driving pathological ECM accumulation. Transforming growth factor-beta (TGFβ) is a well-established regulator of fibroblast activation; however, the precise molecular mechanisms, particularly the involvement of ion channels, remain poorly understood. Emerging evidence highlights the regulatory role of ion channels, including calcium-activated potassium (KCa) channels, in fibroblast activation. This study elucidates the role of ion channels and investigates the mechanism by which Yoda1, an agonist of the mechanosensitive ion channel Piezo1, modulates TGFβ-induced fibroblast activation. Using NIH/3T3 fibroblasts, we demonstrated that TGFβ-induced activation is regulated by tetraethylammonium (TEA)-sensitive potassium channels, but not by specific K⁺ channel subtypes such as BK, SK, or IK channels. Intriguingly, Yoda1 was found to inhibit TGFβ-induced fibroblast activation through a Piezo1-independent mechanism. Transcriptomic analysis revealed that Yoda1 modulates fibroblast activation by altering gene expression pathways associated with fibrotic processes. Bromodomain-containing protein 4 (BRD4) was identified as a critical mediator of Yoda1’s effects, as pharmacological inhibition of BRD4 with JQ1 or ZL0454 suppressed TGFβ-induced expression of the fibroblast activation marker Periostin (Postn). Conversely, BRD4 overexpression attenuated the inhibitory effects of Yoda1 in both mouse and rat CFs. These results provide novel insights into the pharmacological modulation of TGFβ-induced cardiac fibroblast activation and highlight promising therapeutic targets for the treatment of fibrosis-related cardiac pathologies. Full article
(This article belongs to the Section Cells of the Cardiovascular System)
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28 pages, 933 KiB  
Review
Therapeutic Horizons: Gut Microbiome, Neuroinflammation, and Epigenetics in Neuropsychiatric Disorders
by Shabnam Nohesara, Hamid Mostafavi Abdolmaleky, Ahmad Pirani and Sam Thiagalingam
Cells 2025, 14(13), 1027; https://doi.org/10.3390/cells14131027 - 4 Jul 2025
Viewed by 265
Abstract
Neuroinflammation is a hallmark of many neuropsychiatric disorders (NPD), which are among the leading causes of disability worldwide. Emerging evidence highlights the significant role of the gut microbiota (GM)–immune system–brain axis in neuroinflammation and the pathogenesis of NPD, primarily through epigenetic mechanisms. Gut [...] Read more.
Neuroinflammation is a hallmark of many neuropsychiatric disorders (NPD), which are among the leading causes of disability worldwide. Emerging evidence highlights the significant role of the gut microbiota (GM)–immune system–brain axis in neuroinflammation and the pathogenesis of NPD, primarily through epigenetic mechanisms. Gut microbes and their metabolites influence immune cell activity and brain function, thereby contributing to neuroinflammation and the development and progression of NPD. The enteric nervous system, the autonomic nervous system, neuroendocrine signaling, and the immune system all participate in bidirectional communication between the gut and the brain. Importantly, the interaction of each of these systems with the GM influences epigenetic pathways. Here, we first explore the intricate relationship among intestinal microbes, microbial metabolites, and immune cell activity, with a focus on epigenetic mechanisms involved in NPD pathogenesis. Next, we provide background information on the association between inflammation and epigenetic aberrations in the context of NPD. Additionally, we review emerging therapeutic strategies—such as prebiotics, probiotics, methyl-rich diets, ketogenic diet, and medications—that may modulate the GM–immune system–brain axis via epigenetic regulation for the prevention or treatment of NPD. Finally, we discuss the challenges and future directions in investigating the critical role of this axis in mental health. Full article
(This article belongs to the Special Issue Interplay Between Intestinal Bacteria and Epigenetic Markers in Pathogenesis of Metabolic and Neuropsychiatric Disorders)
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24 pages, 6515 KiB  
Article
The Effects of Different Types of Exercise on Pulmonary Inflammation and Fibrosis in Mice with Type 2 Diabetes Mellitus
by Haoyang Gao, Xiaotong Ma, Ze Wang, Danlin Zhu, Yifan Guo, Linlin Zhao and Weihua Xiao
Cells 2025, 14(13), 1026; https://doi.org/10.3390/cells14131026 - 4 Jul 2025
Viewed by 279
Abstract
Background: Diabetic lung disease, characterized by inflammation and fibrosis, is an emerging chronic complication of type 2 diabetes mellitus (T2DM). However, systematic studies on the effects of exercise interventions remain limited. This study aimed to investigate the impact of different exercise types (swimming, [...] Read more.
Background: Diabetic lung disease, characterized by inflammation and fibrosis, is an emerging chronic complication of type 2 diabetes mellitus (T2DM). However, systematic studies on the effects of exercise interventions remain limited. This study aimed to investigate the impact of different exercise types (swimming, resistance training, and high-intensity interval training [HIIT]) on pulmonary inflammation and fibrosis in T2DM mice, and to explore underlying molecular mechanisms. Methods: A T2DM mouse model was established by a high-fat diet (HFD) combined with streptozotocin (STZ) induction. Mice were randomly divided into sedentary control, swimming, resistance training, and HIIT groups, and underwent 8 weeks of exercise intervention. After the intervention, body composition was assessed. Lung histopathological changes were evaluated by hematoxylin&eosin (HE) and Masson staining. Inflammatory cytokines, fibrosis markers, and the expression of the TGF-β1/Smad signaling pathway were detected. Macrophage infiltration and polarization were also analyzed. Results: Exercise intervention improved body composition and reduced oxidative stress in T2DM mice. All three exercise modalities downregulated inflammatory cytokine expression, inhibited macrophage activation and M1 polarization, and promoted M2 polarization. Additionally, exercise improved lung tissue structure, reduced collagen deposition, and decreased the expression of fibrosis-related markers. Furthermore, anti-fibrotic effects were mediated by suppression of the TGF-β1/Smad signaling pathway and inhibition of epithelial-mesenchymal transition (EMT). Among the interventions, HIIT demonstrated the strongest inhibitory effect on the TGF-β1/Smad pathway, while swimming showed the most significant anti-inflammatory benefits. Conclusions: Different types of exercise effectively alleviate pulmonary inflammation and fibrosis in T2DM mice. These effects are closely related to the inhibition of oxidative stress, regulation of macrophage polarization, and suppression of TGF-β1/Smad signaling activation, with swimming and HIIT demonstrating superior protective benefits. Full article
(This article belongs to the Special Issue Diabetes-Induced Organ Damage: Cellular Mechanisms and Therapeutic Opportunities)
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19 pages, 2007 KiB  
Review
Emerging Biomarker Potential of Extracellular Vesicle-Enclosed MicroRNAs for Liver Fibrosis Detection
by Sharmila Fagoonee, Valeria Menchise, Daniela Delli Castelli and Stefania Bruno
Cells 2025, 14(13), 1025; https://doi.org/10.3390/cells14131025 - 4 Jul 2025
Viewed by 239
Abstract
Liver fibrosis is a frequent pathological outcome of long-term liver diseases, arising from sustained damage to the liver. Two main types of liver damage can trigger fibrotic progression: hepatocellular injury, often caused by viral infections, alcohol, or metabolic disorders, and cholestatic injury, associated [...] Read more.
Liver fibrosis is a frequent pathological outcome of long-term liver diseases, arising from sustained damage to the liver. Two main types of liver damage can trigger fibrotic progression: hepatocellular injury, often caused by viral infections, alcohol, or metabolic disorders, and cholestatic injury, associated with impaired bile flow due to autoimmune or congenital conditions. Despite diverse etiologies, liver fibrosis exhibits conserved biological processes, including hepatocyte death, chronic inflammation, disruption of epithelial or endothelial barriers, and excessive deposition of extracellular matrix (ECM) components. These coordinated events reflect the complex interplay among parenchymal damage, immune activation, and fibrogenic signaling pathways. If unresolved, fibrosis may progress to cirrhosis, liver failure, or hepatocellular carcinoma. In the pursuit of non-invasive biomarkers for early detection and monitoring of fibrosis, extracellular vesicles (EVs) have garnered significant attention. Among the diverse cargoes within EVs, microRNAs (miRNAs) have emerged as particularly promising due to their stability, disease-specific expression patterns, and involvement in fibrogenic signaling. This review explores the role of EV-associated miRNAs in liver fibrosis, highlighting key candidates implicated in hepatocellular and cholestatic injury and their clinical potential as diagnostic and prognostic biomarkers, with special focus on MAFLD/MASH, primary sclerosing cholangitis, primary biliary cholangitis, and biliary atresia as representatives. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Biomarkers for Human Disease)
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22 pages, 3822 KiB  
Article
Human Extravillous Trophoblasts Require SRC-2 for Sustained Viability, Migration, and Invasion
by Vineet K. Maurya, Pooja Popli, Bryan C. Nikolai, David M. Lonard, Ramakrishna Kommagani, Bert W. O’Malley and John P. Lydon
Cells 2025, 14(13), 1024; https://doi.org/10.3390/cells14131024 - 4 Jul 2025
Viewed by 237
Abstract
Defective placentation is a recognized etiology for several gestational complications that include early pregnancy loss, preeclampsia, and intrauterine growth restriction. Sustained viability, migration, and invasion are essential cellular properties for embryonic extravillous trophoblasts to execute their roles in placental development and function, while [...] Read more.
Defective placentation is a recognized etiology for several gestational complications that include early pregnancy loss, preeclampsia, and intrauterine growth restriction. Sustained viability, migration, and invasion are essential cellular properties for embryonic extravillous trophoblasts to execute their roles in placental development and function, while derailment of these cellular processes is linked to placental disorders. Although the cellular functions of extravillous trophoblasts are well recognized, our understanding of the pivotal molecular determinants of these functions is incomplete. Using the HTR-8/SVneo immortalized human extravillous trophoblast cell line, we report that steroid receptor coactivator-2 (SRC-2), a coregulator of transcription factor-mediated gene expression, is essential for extravillous trophoblast cell viability, motility, and invasion. Genome-scale transcriptomics identified an SRC-2-dependent transcriptome in HTR-8/SVneo cells that encodes a diverse spectrum of proteins involved in placental tissue development and function. Underscoring the utility of this transcriptomic dataset, we demonstrate that WNT family member 9A (WNT 9A) is not only regulated by SRC-2 but is also crucial for maintaining many of the above SRC-2-dependent cellular functions of human extravillous trophoblasts. Full article
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18 pages, 836 KiB  
Systematic Review
The Interplay Between Autoimmune Disorders Affecting the Coagulation and Platelet Systems and Their Implications for Cardiovascular Diseases: A Systematic Review
by Kiana Mohammadian, Melika Asayesh, Fatemeh Fakhar, Shayan Keramat and Agata Stanek
Cells 2025, 14(13), 1023; https://doi.org/10.3390/cells14131023 - 4 Jul 2025
Viewed by 237
Abstract
Autoimmune diseases (AIDs) are chronic, heterogeneous conditions developing from an aberrant immune response, impacting particular organs or multiple systems. This systematic review attempted to investigate and evaluate the correlation between autoimmune diseases and cardiovascular disease (CVD), emphasizing immunological and pathophysiological mechanisms. A comprehensive [...] Read more.
Autoimmune diseases (AIDs) are chronic, heterogeneous conditions developing from an aberrant immune response, impacting particular organs or multiple systems. This systematic review attempted to investigate and evaluate the correlation between autoimmune diseases and cardiovascular disease (CVD), emphasizing immunological and pathophysiological mechanisms. A comprehensive search for relevant research was conducted on the PubMed, SCOPUS, and ScienceDirect databases, resulting in the identification of 28 studies that met the inclusion criteria. Of the cohort studies, 26 (92.8%) demonstrated a significant association between autoimmune diseases and increased cardiovascular risk. The major mechanisms include chronic inflammation, endothelial dysfunction, oxidative stress, and immune cell dysregulation. Essential biological components, including T cells, B cells, and neutrophils, were identified as contributors to atherosclerotic processes through cytokine secretion, expression of adhesion molecules, and thrombogenic activity. In contrast, two studies (7.1%) found no statistically significant association. In conclusion, autoimmune diseases significantly increase cardiovascular risk through complicated immunological mechanisms. Comprehending these pathways could influence future therapeutic approaches to reduce cardiovascular complications in affected patients. Full article
(This article belongs to the Special Issue New Research on Immunity and Inflammation in Cardiovascular Disease)
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16 pages, 5036 KiB  
Article
Hyperalgesia in the Psychological Stress-Induced Fibromyalgia Model Shows Sexual Dimorphism Mediated by LPA1 and LPA3
by Hiroshi Ueda, Hiroyuki Neyama, Naoki Dozono, Junken Aoki and Jerold Chun
Cells 2025, 14(13), 1022; https://doi.org/10.3390/cells14131022 - 4 Jul 2025
Viewed by 217
Abstract
Since the initial report indicating that LPA1 signaling plays a key role in initiating nerve injury-induced neuropathic pain (NeuP), subsequent studies using knockout mice and LPA1/3 antagonists have demonstrated that LPA1 and LPA3 signaling impact NeuP and fibromyalgia (FM) [...] Read more.
Since the initial report indicating that LPA1 signaling plays a key role in initiating nerve injury-induced neuropathic pain (NeuP), subsequent studies using knockout mice and LPA1/3 antagonists have demonstrated that LPA1 and LPA3 signaling impact NeuP and fibromyalgia (FM) models. In the present study, we identified hyperalgesia sexual dimorphism involving LPA1/3 signaling in the intermittent psychological stress induced-related FM-like model called intermittent psychological stress (IPS)-induced generalized pain (IPGP) model where the hyperalgesia in IPGP mice was abolished in LPA1- and LPA3-knock-out mice. Pharmacological intervention by intraperitoneal (i.p.) treatments with the LPA1/3 antagonist Ki16425 consistently prevented hyperalgesia. However, intracerebroventricular treatments with Ki16425 abolished hyperalgesia in male, but not female, mice. Notably, intrathecal treatments of Ki16425 did not prevent hyperalgesia. Further studies revealed that splenocytes derived from female IPGP mice could initiate hyperalgesia via adoptive transfer in naïve mice, and this effect was abolished when donor mice were pre-treated with Ki16425 (i.p.). Thus, these studies identify male-specific LPA1/3-mediated mechanisms in the brain underlying IPGP, as well as distinct LPA-LPA1/3-mediated peripheral immune mechanisms. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain)
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19 pages, 14082 KiB  
Article
Macrophage EP4 Deficiency Drives Atherosclerosis Progression via CD36-Mediated Lipid Uptake and M1 Polarization
by Xinyu Tang, Qian Chen, Manli Guo, Ying Wen, Cuiping Jia, Yun Bu, Ting Wang, Yuan Zhang and Waiho Tang
Cells 2025, 14(13), 1021; https://doi.org/10.3390/cells14131021 - 4 Jul 2025
Viewed by 234
Abstract
Atherosclerosis is a chronic inflammatory disease and a major pathological basis of numerous cardiovascular conditions, with a high global mortality rate. Macrophages play a pivotal role in its pathogenesis through phenotypic switching and foam cell formation. Prostaglandin E2 receptor subtype 4 (EP4) highly [...] Read more.
Atherosclerosis is a chronic inflammatory disease and a major pathological basis of numerous cardiovascular conditions, with a high global mortality rate. Macrophages play a pivotal role in its pathogenesis through phenotypic switching and foam cell formation. Prostaglandin E2 receptor subtype 4 (EP4) highly expressed on the macrophage surface, is involved in various pathophysiological processes, such as inflammation and lipid metabolism. However, the role of macrophage EP4 in the progression of atherosclerosis remains unclear. To determine whether macrophage EP4 affects the progression of atherosclerosis by regulating foam cell formation and macrophage polarization. Myeloid-specific EP4 knockout mice with an ApoE-deficient background were fed a Western diet for 16 weeks. Our results showed that EP4 expression was significantly downregulated during atherosclerosis. EP4 deficiency was found to exacerbate atherosclerotic plaque formation and destabilizes plaques. In vitro studies further demonstrated that loss of EP4 in myeloid cells promoted foam cell formation and M1 macrophage polarization. Both transcriptomic and proteomic analysis showed that EP4 may regulate these processes by regulating CD36 expression in macrophage, which was further confirmed by Western blot and qPCR. In summary, deficiency of EP4 receptor in macrophages enhance foam cell formation and M1 polarization by upregulating CD36 expression, thereby accelerating the progression of atherosclerosis. Full article
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2 pages, 980 KiB  
Correction
Correction: Ferraresi et al. Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy. Cells 2021, 10, 3213
by Alessandra Ferraresi, Andrea Esposito, Carlo Girone, Letizia Vallino, Amreen Salwa, Ian Ghezzi, Suyanee Thongchot, Chiara Vidoni, Danny N. Dhanasekaran and Ciro Isidoro
Cells 2025, 14(13), 1020; https://doi.org/10.3390/cells14131020 - 4 Jul 2025
Viewed by 103
Abstract
In the original publication [...] Full article
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12 pages, 7448 KiB  
Article
An Old New Friend: Folliculo-Stellate Cells in Pituitary Neuroendocrine Tumors
by Valeria-Nicoleta Nastase, Iulia Florentina Burcea, Roxana Ioana Dumitriu-Stan, Amalia Raluca Ceausu, Flavia Zara, Catalina Poiana and Marius Raica
Cells 2025, 14(13), 1019; https://doi.org/10.3390/cells14131019 - 3 Jul 2025
Viewed by 218
Abstract
Pituitary neuroendocrine tumors (PitNETs) represent a complex pathology based on numerous incompletely elucidated molecular mechanisms. Beyond tumor cells, analyzing the tumor microenvironment may help identify novel prognostic markers and therapies. A key component of this environment is the folliculo-stellate (FS) cell. We examined [...] Read more.
Pituitary neuroendocrine tumors (PitNETs) represent a complex pathology based on numerous incompletely elucidated molecular mechanisms. Beyond tumor cells, analyzing the tumor microenvironment may help identify novel prognostic markers and therapies. A key component of this environment is the folliculo-stellate (FS) cell. We examined FS cells in 77 PitNETs obtained by transsphenoidal surgery, using glial fibrillary acidic protein (GFAP) as an immunohistochemical marker. Immunohistochemistry for anterior pituitary hormones and transcription factors was performed to accurately classify the tumors. Our study included 19 somatotroph, 16 mammosomatotroph, 5 plurihormonal PIT-1 positive, 7 corticotroph, 14 gonadotroph, 11 unusual plurihormonal, and 5 null cell PitNETs. FS cells were observed in 55 of the cases, distributed isolated, in small groups or diffuse networks. A considerable number of tumors immunopositive for more than one hormone (including associations between GH/PRL, but also unusual combinations like GH/ACTH) also contained FS cells (p < 0.01), suggesting their involvement in tumor lineages differentiation. In 27 tumors, GFAP-positive cells clustered in highly vascularized areas. Additionally, in 11 of these cases a direct interaction between endothelial cells and FS cells was noted, sustaining their potential role in tumor angiogenesis. Given their complexity, FS cells may be crucial for understanding tumorigenesis mechanisms. Full article
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15 pages, 719 KiB  
Review
Mesenchymal Stem-Cell-Derived Exosomes and MicroRNAs: Advancing Cell-Free Therapy in Systemic Sclerosis
by Cristiano Barbetta, Francesco Bonomi, Gemma Lepri, Daniel E. Furst, Silvia Bellando Randone and Serena Guiducci
Cells 2025, 14(13), 1018; https://doi.org/10.3390/cells14131018 - 3 Jul 2025
Viewed by 224
Abstract
Mesenchymal stem cell (MSC) transplantation has emerged as a potential therapeutic strategy for systemic sclerosis (SSc), a rare autoimmune disease characterized by inflammation, fibrosis, and vasculopathy. Recent evidence suggests that the therapeutic benefits of MSCs do not depend directly on their ability to [...] Read more.
Mesenchymal stem cell (MSC) transplantation has emerged as a potential therapeutic strategy for systemic sclerosis (SSc), a rare autoimmune disease characterized by inflammation, fibrosis, and vasculopathy. Recent evidence suggests that the therapeutic benefits of MSCs do not depend directly on their ability to proliferate but rather on their capacity to release extracellular nanovesicles known as exosomes (MSC-Exos). MSC-Exos are rich in bioactive molecules such as microRNAs, which can modulate gene expression and trigger significant biological responses, playing a central role in modulating immune responses, inhibiting fibrotic pathways and promoting tissue repair and angiogenesis. Preclinical studies have demonstrated that MSC-Exos can attenuate fibrosis, modulate macrophage polarization, suppress autoreactive lymphocyte activity, and even reverse pulmonary arterial hypertension in animal models of SSc. Compared to cell-based therapies, MSC-Exos offer several advantages, including lower immunogenicity and better safety profile. This review provides an overview of the immunomodulatory, antifibrotic, and angiogenic properties of MSC-Exos and explores their potential as novel cell-free therapy for SSc. Full article
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15 pages, 2238 KiB  
Article
The Phosphodiesterase 4 Inhibitor Roflumilast Protects Microvascular Endothelial Cells from Irradiation-Induced Dysfunctions
by Nathalie Guitard, Florent Raffin and François-Xavier Boittin
Cells 2025, 14(13), 1017; https://doi.org/10.3390/cells14131017 - 3 Jul 2025
Viewed by 171
Abstract
In endothelial cells, high-dose irradiation induces numerous dysfunctions including alteration in junctional proteins such as VE-Cadherin, apoptosis and enhanced adhesiveness linked to overexpression of adhesion molecules like Intercellular Adhesion Molecule 1 (ICAM-1). Such endothelial dysfunctions can lead to altered tissue perfusion, development of [...] Read more.
In endothelial cells, high-dose irradiation induces numerous dysfunctions including alteration in junctional proteins such as VE-Cadherin, apoptosis and enhanced adhesiveness linked to overexpression of adhesion molecules like Intercellular Adhesion Molecule 1 (ICAM-1). Such endothelial dysfunctions can lead to altered tissue perfusion, development of tissue inflammation through increased endothelial permeability, and ultimately organ damage. As intracellular cyclic AMP (cAMP) levels are known to control intercellular junctions or apoptosis in the endothelium, we investigated here the effect of the Phosphodiesterase 4 inhibitor Roflumilast, a drug increasing cAMP levels, on irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). Using continuous impedance measurements in confluent endothelial cell monolayers, Roflumilast was found to rapidly reinforce the endothelial barrier and to prevent irradiation-induced barrier disruption. In accordance, irradiation-induced alteration in membrane VE-Cadherin-composed adherens junctions was prevented by Roflumilast treatment after irradiation, which was correlated with its protective effect of the actin cytoskeleton. Post-irradiation treatment with Roflumilast also protected HPMECs from irradiation-induced late apoptosis, but was without effect on irradiation-induced ICAM-1 overexpression. Overall, our results indicate that the beneficial effects of Roflumilast after irradiation are linked to the strengthening/protection of the endothelial barrier and reduced apoptosis, suggesting that this medicine may be useful for the treatment of endothelial damages after exposure to a high dose of radiation. Full article
(This article belongs to the Section Cellular Pathology)
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25 pages, 2864 KiB  
Review
Post-Translational Modification of p62: Roles and Regulations in Autophagy
by Shuai Xiao, Yeping Yu, Meng Liao, Dandan Song, Xiaozhen Xu, Lingli Tian, Rui Zhang, Hao Lyu, Dong Guo, Qi Zhang, Xing-Zhen Chen, Cefan Zhou and Jingfeng Tang
Cells 2025, 14(13), 1016; https://doi.org/10.3390/cells14131016 - 2 Jul 2025
Viewed by 176
Abstract
Autophagy is a highly conserved cellular process that plays a crucial role in maintaining cellular homeostasis by degrading damaged organelles, misfolded proteins, and other cellular components. p62/SQSTM1 functions as a selective autophagy receptor by binding polyubiquitinated cargo through its UBA domain and linking [...] Read more.
Autophagy is a highly conserved cellular process that plays a crucial role in maintaining cellular homeostasis by degrading damaged organelles, misfolded proteins, and other cellular components. p62/SQSTM1 functions as a selective autophagy receptor by binding polyubiquitinated cargo through its UBA domain and linking it to microtubule-associated protein light chain 3 (LC3)-decorated autophagosomes. Moreover, p62 acts as a signaling hub and is essential in response to various stressors, including nutrient deprivation and oxidative stress. Post-translational modifications (PTMs) critically regulate p62’s multifaceted roles, controlling p62’s phase separation, cargo recruitment, signaling interactions, and autophagic degradation efficiency. The dysregulation of p62 PTMs is closely related to the occurrence and development of human diseases, particularly neurodegenerative disorders and certain cancers. This review summarizes the main PTM events of p62 discovered to date that influence the autophagy process, including phosphorylation, acetylation, ubiquitination, and S-acylation, as well as their known contributions to protein aggregation and disease. The PTMs of p62 dynamically regulate autophagy, protein aggregation, and cellular signaling, underscoring its importance as a potential therapeutic target and biomarker for these diseases. Full article
(This article belongs to the Section Autophagy)
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19 pages, 5712 KiB  
Article
Regulation of Mitochondrial Metabolism by Mfn1 Gene Encoding Mitofusin Affects Cellular Proliferation and Histone Modification
by Han Xu, Xiaoyu Zhao, Yuan Yun, Yuxin Gao, Chunjie Bo, Lishuang Song, Chunling Bai, Lei Yang, Guangpeng Li and Guanghua Su
Cells 2025, 14(13), 1015; https://doi.org/10.3390/cells14131015 - 2 Jul 2025
Viewed by 174
Abstract
Mitochondria maintain cellular homeostasis through the dynamic balance of fusion and fission, which relies on nuclear-encoded mitochondrial fusion proteins, mitofusins 1 and 2 (Mfn1, Mfn2). Changes in Mfn1 and Mfn2 expression significantly affect mitochondrial fusion and fission, thereby affecting cellular metabolism. This study [...] Read more.
Mitochondria maintain cellular homeostasis through the dynamic balance of fusion and fission, which relies on nuclear-encoded mitochondrial fusion proteins, mitofusins 1 and 2 (Mfn1, Mfn2). Changes in Mfn1 and Mfn2 expression significantly affect mitochondrial fusion and fission, thereby affecting cellular metabolism. This study investigated the effect of Mfn1 expression on cell proliferation, apoptosis, and mitochondrial function by overexpressing Mfn1 (in OE-Mfn1 cells) and silencing Mfn1 using short hairpin RNA (shRNA) (in shMfn1 cells). Cell proliferation capacity, mitochondrial membrane potential, and mitochondrial ATP content were measured. To investigate the effects of Mfn1 on cellular metabolism and epigenetic modifications, the levels of metabolites α-KG, A-CoA, and SAM, as well as the levels of cellular methylation and acetylation, were detected by ELISA. Differentially expressed genes and metabolites were assessed by RNA-seq and LC-MS. This study demonstrates that alterations in Mfn1 gene expression can significantly affect mitochondrial metabolism and cell proliferation and apoptosis. In addition, Mfn1 affects the expression of genes encoding enzymes that are responsible for histone methylation and acetylation, thereby regulating these modifications. These findings provide a theoretical basis for further elucidation of the mechanisms by which Mfn1 affects cell proliferation, regulates metabolites, and modulates chromatin epigenetic modification. Full article
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28 pages, 1946 KiB  
Review
Understanding Microglia in Mesocorticolimbic Circuits: Implications for the Study of Chronic Stress and Substance Use Disorders
by David B. Nowak, Juan Pablo Taborda-Bejarano, Fernando J. Chaure, John R. Mantsch and Constanza Garcia-Keller
Cells 2025, 14(13), 1014; https://doi.org/10.3390/cells14131014 - 2 Jul 2025
Viewed by 262
Abstract
Exposure to chronic stress creates vulnerability to drug misuse and presents a barrier to sustained recovery for many individuals experiencing substance use disorders (SUDs). Preclinical literature demonstrates that stress modulates psychostimulant intake and seeking, yet there are wide gaps in our understanding of [...] Read more.
Exposure to chronic stress creates vulnerability to drug misuse and presents a barrier to sustained recovery for many individuals experiencing substance use disorders (SUDs). Preclinical literature demonstrates that stress modulates psychostimulant intake and seeking, yet there are wide gaps in our understanding of the specific mechanisms by which stress promotes brain changes that may govern addiction-related behaviors. Recent data suggest that microglia, innate immune cells in the central nervous system, are highly responsive to chronic stressors, and several mechanistic links have been explored highlighting the critical role microglia play in stress-related brain adaptation. Importantly, psychostimulants may engage similar microglial machinery, which opens the door for investigation into how microglia may be involved in shaping motivation for psychostimulants, especially in the context of stress exposure. The aims of this review are threefold: 1. Offer a brief overview of microglial biology in the adult brain. 2. Review current methods of interrogating microglial function with a focus on morphometric analyses. 3. Highlight preclinical research describing how microglia contribute to brain changes following chronic stress and/or psychostimulant exposure. Ultimately, this review serves to prime investigators studying the intersection of stress and SUDs to consider the relevant impacts of microglial actions. Full article
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17 pages, 8515 KiB  
Article
Combined TGF-β3 and FGF-2 Stimulation Enhances Chondrogenic Potential of Ovine Bone Marrow-Derived MSCs
by Sandra Stamnitz, Agnieszka Krawczenko and Aleksandra Klimczak
Cells 2025, 14(13), 1013; https://doi.org/10.3390/cells14131013 - 2 Jul 2025
Viewed by 174
Abstract
Mesenchymal stem cells (MSCs) represent a promising cell source for cartilage tissue engineering due to their chondrogenic potential. However, current differentiation protocols result in limited efficiency. This study assessed the combined effects of transforming growth factor-beta 3 (TGF-β3) and fibroblast growth factor-2 (FGF-2) [...] Read more.
Mesenchymal stem cells (MSCs) represent a promising cell source for cartilage tissue engineering due to their chondrogenic potential. However, current differentiation protocols result in limited efficiency. This study assessed the combined effects of transforming growth factor-beta 3 (TGF-β3) and fibroblast growth factor-2 (FGF-2) on the morphology, proliferation, chondrogenic differentiation, chondrogenic gene expression, and cytokine profile of ovine bone marrow-derived MSCs (BM-MSCs). BM-MSCs were cultured under four conditions: control (αMEM) or αMEM supplemented with FGF-2, TGF-β3, or TGF-β3 + FGF-2. Morphological and proliferation analyses, Alcian blue staining in 2D and 3D, and real-time PCR for early (Chad, Comp, and Sox 5) and late (Agg, Col IX, Sox 9, and Fmod) chondrogenic markers were performed. Cytokine secretion profiles were analyzed using multiplex assay. TGF-β3 induced morphological changes indicative of early chondrogenesis, while FGF-2 enhanced proliferation. The combination of both cytokines led to a synergistic increase in cell proliferation, early and late chondrogenic gene expression, and glycosaminoglycans (GAG) deposition. Cytokine analysis revealed that TGF-β3 enhanced the immunomodulatory and angiogenic profile of BM-MSCs, whereas co-treatment with FGF-2 yielded a balanced and potentially regenerative secretome. Dual stimulation with TGF-β3 and FGF-2 significantly improves the chondrogenic differentiation of ovine BM-MSCs by enhancing both molecular and functional markers of cartilage formation. Full article
(This article belongs to the Special Issue Modelling Tissue Microenvironments in Development and Disease)
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18 pages, 908 KiB  
Review
The Role of Protein Ubiquitination in the Onset and Progression of Sepsis
by Meng-Yan Chen, Yang Liu and Min Fang
Cells 2025, 14(13), 1012; https://doi.org/10.3390/cells14131012 - 2 Jul 2025
Viewed by 239
Abstract
Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, with complex pathophysiological mechanisms. As an important post-translational modification, protein ubiquitination exhibits multiple non-traditional functions in sepsis beyond its conventional role in protein degradation. Regulating the network of inflammatory cytokines, [...] Read more.
Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, with complex pathophysiological mechanisms. As an important post-translational modification, protein ubiquitination exhibits multiple non-traditional functions in sepsis beyond its conventional role in protein degradation. Regulating the network of inflammatory cytokines, the dynamic balance of immune cells and organ-specific protective pathways is deeply involved in the pathological process of sepsis. This review focuses on the unconventional roles of protein ubiquitination in sepsis, including its regulation of the inflammatory response, immune cell functions, and organ protection. It systematically summarizes the regulatory mechanisms of ubiquitination in the non-degradative activation of the nuclear factor kappa B (NF-κB) signaling pathway, the dynamic assembly of the NLRP3 inflammasome, the reprogramming of macrophage polarization, and the injuries of organs such as the heart, liver, and lungs. These processes demonstrate that ubiquitination serves as a pivotal nexus between immunological dysregulation and multi-organ impairment in sepsis. This review suggests that targeting non-degradative ubiquitination alterations may provide viable therapeutic options to mitigate excessive inflammation and organ failure in sepsis. Full article
(This article belongs to the Special Issue Non-Traditional Roles of Protein Ubiquitination in Cellular Processes and Health)
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30 pages, 3854 KiB  
Article
Apolipoprotein L1 (APOL1): Consideration of Molecular Evolution, Interaction with APOL3, and Impact of Splice Isoforms Advances Understanding of Cellular and Molecular Mechanisms of Cell Injury
by Razi Khalaila and Karl Skorecki
Cells 2025, 14(13), 1011; https://doi.org/10.3390/cells14131011 - 2 Jul 2025
Viewed by 153
Abstract
The Apolipoprotein L1 (APOL1) innate immunity gene product represents the sole member of the APOL gene family in humans capable of secretion into circulation, thereby mediating the trypanolysis of T. brucei brucei. Gain-of-function variants of the APOL1 gene originated and spread among [...] Read more.
The Apolipoprotein L1 (APOL1) innate immunity gene product represents the sole member of the APOL gene family in humans capable of secretion into circulation, thereby mediating the trypanolysis of T. brucei brucei. Gain-of-function variants of the APOL1 gene originated and spread among human population groups to extend APOL1’s protective capacity to include also serum-resistant subspecies, such as T. brucei gambiense (S342G known as APOL1-G1) and T. brucei rhodesiense (N388_Y389del known as APOL1-G2). The biochemical pathways underlying the lytic activity of these evolutionary favored mutations against bloodstream trypanosomes have been elucidated with remarkable precision. However, the intricate molecular mechanisms by which such variants confer an increased susceptibility to renal cellular injury and consequent kidney disease remain incompletely defined. In the absence of a consistent mechanistic explanation for differential kidney injury, we propose pursuing three interrelated avenues of investigation informed by prior epidemiological and mechanistic evidence linking them to APOL1’s cytotoxicity: (1) Molecular evolution of APOL1 haplotypes in human populations, (2) APOL1 splicing and consequent splice isoforms, (3) Interaction of APOL1 with other APOL gene family members, prioritizing APOL3. In the current study, we use reanalysis of population genetics datasets to resolve the haplotype contexts of all protein-altering APOL1 variants, uncovering previously unrecognized variant–haplotype couplings. We further characterize distinct cellular physiological properties among APOL1 splice isoforms, stressing the importance of isoform vB and what can be learned from isoform vC. Finally, a native interaction, and its interface, between APOL1 and APOL3 is reported, and shown to be differentially modulated by G1 and G2. We contend that continuing studies integrating these three interrelated domains will substantially advance mechanistic insights into APOL1 variant-driven renal injury, and leverage the findings to provide a more cohesive framework to guide future research. Full article
(This article belongs to the Special Issue Evolution, Structure, and Functions of Apolipoproteins L)
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19 pages, 5275 KiB  
Article
Ciprofloxacin Exerts Anti-Tumor Effects In Vivo Through cGAS-STING Activation and Modulates Tumor Microenvironment
by Jian-Syun Chen, Chih-Wen Chi, Cheng-Ta Lai, Shu-Hua Wu, Hui-Ru Shieh, Jiin-Cherng Yen and Yu-Jen Chen
Cells 2025, 14(13), 1010; https://doi.org/10.3390/cells14131010 - 2 Jul 2025
Viewed by 160
Abstract
Immunotherapy targeting the immune functions of the tumor microenvironment (TME) is beneficial for colorectal cancer; however, the response rate is poor. Ciprofloxacin is a fluoroquinolone-class antibiotic that is used to treat bacterial infections. The purpose of this study is to assess the mechanism [...] Read more.
Immunotherapy targeting the immune functions of the tumor microenvironment (TME) is beneficial for colorectal cancer; however, the response rate is poor. Ciprofloxacin is a fluoroquinolone-class antibiotic that is used to treat bacterial infections. The purpose of this study is to assess the mechanism of ciprofloxacin that enhances anti-PD1 in colorectal cancer. We found that ciprofloxacin induced cytosolic DNA, including single-stranded and double-stranded DNA, formation in mouse CT26 colorectal adenocarcinoma cells. Molecules in DNA-sensing signaling such as cGAS, STING, and IFNβ mRNA and protein expression were elicited after ciprofloxacin treatment in CT26 cells. STING siRNA abrogated the cGAS-STING pathway activation by ciprofloxacin. In vivo, ciprofloxacin exhibited a synergistic effect with anti-PD1 to suppress tumor growth in a CT26 syngeneic animal model without biological toxicity. The examination of TME revealed that ciprofloxacin, alone and in combination therapy, induced M1 and red pulp macrophage production in the spleen. In tumors, M1 and M2 macrophage levels were increased by ciprofloxacin, and CD8+ T cell granzyme B expression was increased after combination therapy. STING showed the highest expression in tumor specimens after combination treatment. Ciprofloxacin may enhance the anti-PD1 efficacy and modulate the TME through the cGAS-STING pathway. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Anti-Cancer Therapies)
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37 pages, 2295 KiB  
Review
The Pathophysiological Role of Vascular Smooth Muscle Cells in Abdominal Aortic Aneurysm
by Dou Shi, Mo Zhang, Yuhan Zhang, Yang Shi, Xing Liu, Xianxian Wu and Zhiwei Yang
Cells 2025, 14(13), 1009; https://doi.org/10.3390/cells14131009 - 2 Jul 2025
Viewed by 442
Abstract
Abdominal aortic aneurysm (AAA) is the most common aortic disease occurring below the renal arteries, caused by multiple etiologies. Currently, no effective drug treatment exists, and the specific pathogenesis remains unclear. Due to its insidious onset and diagnostic challenges, AAA often culminates in [...] Read more.
Abdominal aortic aneurysm (AAA) is the most common aortic disease occurring below the renal arteries, caused by multiple etiologies. Currently, no effective drug treatment exists, and the specific pathogenesis remains unclear. Due to its insidious onset and diagnostic challenges, AAA often culminates in aortic rupture, which has a high mortality rate. During AAA development, vascular smooth muscle cells (VSMCs) undergo significant pathological alterations, including contractile dysfunction, phenotypic modulation, cellular degradation, and heightened inflammatory and oxidative stress responses. In particular, emerging evidence implicates vascular smooth muscle cell (VSMC) metabolic dysregulation and mitochondrial dysfunction as key contributors to AAA progression. In this review, we systematically summarize the current understanding of VSMC biology, including their developmental origins, structural characteristics, and functional roles in aortic wall homeostasis, along with the regulatory networks governing the VSMC phenotype and functional maintenance. This review highlights the urgent need for further investigation into the aortic wall VSMC pathophysiology to identify novel therapeutic targets for AAA. These insights may pave the way for innovative treatment strategies in aortic disease management. Full article
(This article belongs to the Section Cellular Biophysics)
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