Cells

41 pages, 2626 KB

Open AccessReview

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

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

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

Abstract

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

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

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

23 pages, 819 KB

Open AccessReview

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

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

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

Abstract

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

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

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

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22 pages, 5775 KB

Open AccessArticle

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

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

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

Abstract

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

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

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

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14 pages, 588 KB

Open AccessReview

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

by Kunitoshi Uchida and Mari Iwase

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

Abstract

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

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

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

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33 pages, 26227 KB

Open AccessArticle

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

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

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

Abstract

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

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

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

18 pages, 2290 KB

Open AccessFeature PaperArticle

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

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

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

Abstract

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

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

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

43 pages, 8860 KB

Open AccessArticle

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

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

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

Abstract

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

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

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

15 pages, 3739 KB

Open AccessArticle

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

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

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

Abstract

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

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

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

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41 pages, 16972 KB

Open AccessSystematic Review

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

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

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

Abstract

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

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

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20 pages, 9732 KB

Open AccessArticle

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

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

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

Abstract

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

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

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

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22 pages, 4698 KB

Open AccessArticle

Neuroimmune Activation in a Goat Model of Intervertebral Disc Degeneration

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

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

Abstract

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

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

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

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17 pages, 1818 KB

Open AccessArticle

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

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

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

Abstract

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

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

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

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21 pages, 3180 KB

Open AccessArticle

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

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

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

Abstract

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

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

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

19 pages, 4511 KB

Open AccessArticle

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

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

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

Abstract

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

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

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

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18 pages, 3407 KB

Open AccessArticle

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

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

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

Abstract

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

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

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

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22 pages, 11282 KB

Open AccessArticle

Effects of N-Acetylcysteine and Alpha-Ketoglutarate on OVCAR3 Ovarian Cancer Cells: Insights from Integrative Bioinformatics and Experimental Validation

by Yasaman Khamineh, Sanaz Panahi-Alanagh, Samaneh Zolghadri, Laleh Mavaddatiyan, Ireneusz Ryszkiel, Agata Stanek and Mahmood Talkhabi

Cells 2026, 15(3), 281; https://doi.org/10.3390/cells15030281 - 2 Feb 2026

Abstract

Ovarian cancer remains one of the leading causes of cancer-related mortality among women, underscoring the need for novel combination strategies that effectively inhibit tumor cell growth while limiting adverse effects. N-acetylcysteine (NAC) and alpha-ketoglutarate (AKG) are biologically active compounds with reported anticancer properties; [...] Read more.

Ovarian cancer remains one of the leading causes of cancer-related mortality among women, underscoring the need for novel combination strategies that effectively inhibit tumor cell growth while limiting adverse effects. N-acetylcysteine (NAC) and alpha-ketoglutarate (AKG) are biologically active compounds with reported anticancer properties; however, their combined effects in ovarian cancer are not well characterized. In this study, we applied an integrative approach combining network pharmacology analysis with in vitro experiments to investigate the effects of NAC and AKG on OVCAR3 ovarian cancer cells. Common molecular targets of NAC and AKG were identified by intersecting predicted compound targets with ovarian cancer-associated genes, followed by protein–protein interaction network construction and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Experimental validation assessed the effects of NAC and AKG, alone and in combination, on cell viability, apoptosis, migration, and clonogenic capacity. Network analysis identified 70 shared target genes enriched in pathways related to apoptosis, cellular stress responses, and cell migration. In vitro experiments demonstrated that combined treatment with NAC (10 mM) and AKG (100 µM) significantly reduced cell viability, increased apoptotic cell death, and markedly suppressed cell migration and colony formation compared with single-agent treatments. Overall, these findings indicate that the combination of NAC and AKG exerts enhanced inhibitory effects on ovarian cancer cell growth and motility in vitro. Full article

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

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12 pages, 427 KB

Open AccessArticle

Interleukin-38: A Candidate Biomarker for Disease Severity in Advanced Steatotic Liver Disease

by Valeria Wagner, Michael Mederer, Barbara Enrich, Veronika Cibulkova, Johanna Piater, Andreas Zollner, Rebecca Giquel-Fernandes, Herbert Tilg and Maria Effenberger

Cells 2026, 15(3), 280; https://doi.org/10.3390/cells15030280 - 2 Feb 2026

Abstract

Background: Interleukin-38 (IL-38) is an anti-inflammatory IL-1—family cytokine implicated in limiting tissue injury by its anti-inflammatory character. We evaluated the diagnostic discrimination and prognostic relevance in steatotic liver disease (SLD). Methods: We conducted a prospective, monocentric cohort analysis of 184 patients with SLD [...] Read more.

Background: Interleukin-38 (IL-38) is an anti-inflammatory IL-1—family cytokine implicated in limiting tissue injury by its anti-inflammatory character. We evaluated the diagnostic discrimination and prognostic relevance in steatotic liver disease (SLD). Methods: We conducted a prospective, monocentric cohort analysis of 184 patients with SLD (n = 176) and healthy controls (n = 8). We tested group differences using Mann–Whitney U or Kruskal–Wallis; determined diagnostic quality using ROC curves. Logistic regression was used to assess the relationship with decompensation. Associations with MELD and routine laboratory parameters were modeled using Spearman correlation and linear regression. We analyzed survival using Kaplan–Meier and Cox regression. Findings: IL-38 concentrations were found to be higher in decompensated (n = 94) than in compensated patients (n = 82) (p < 0.001). MELD was positively associated with IL-38 (p < 0.001; 95% CI 0.057–0.120). This corresponds to a 9.2% increase in IL-38 per 1-point increase in MELD (95% CI 5.9–12.7%). IL-38 correlated positively with the MELD score (p < 0.001) and with bilirubin/AST/LDH. In the combination model (MELD + IL-38 ± CRP), a very good AUC ≈ 0.92 was achieved. Conclusion: IL-38 reflects the severity of steatotic liver disease and is therefore a potentially predictive biomarker for early risk stratification and therapy monitoring. Full article

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15 pages, 1969 KB

Open AccessArticle

Effect of the G-Protein-Coupled Receptor T2R14 on Proliferation and Cell Population Growth in Oral Cancer Cells

by Yongqiang Chen, Manikanta Kella, Kayla Austin, Rajinder P. Bhullar and Prashen Chelikani

Cells 2026, 15(3), 279; https://doi.org/10.3390/cells15030279 - 1 Feb 2026

Abstract

Oral cancer is a leading cause of cancer-related deaths and significantly affects the quality of life of patients. However, many of its mechanisms remain unclear, and its treatment needs improvement. The G-protein-coupled receptor taste receptor type 2 member 14 (T2R14 or TAS2R14) is [...] Read more.

Oral cancer is a leading cause of cancer-related deaths and significantly affects the quality of life of patients. However, many of its mechanisms remain unclear, and its treatment needs improvement. The G-protein-coupled receptor taste receptor type 2 member 14 (T2R14 or TAS2R14) is expressed in various cancer types. However, few studies have investigated its roles in oral cancer, and its effects on oral cancer cell proliferation and growth are unknown. This study aimed to examine T2R14’s impact on proliferation and cell population growth (CPG) of oral cancer cells. TAS2R14 gene knockout was performed, and cell numbers, cell viability, and colony formation were measured. This study showed that TAS2R14 knockout in oral cancer cells significantly decreased calcium mobilization, increased cell numbers, colony formation, the proliferation marker proliferating cell nuclear antigen, and the phosphorylation of mechanistic target of rapamycin, but did not affect cell viability. These observations are consistent with the clinical data that higher TAS2R14 mRNA expression is associated with better survival of patients with oral cancer. Therefore, T2R14 downregulation increased oral cancer CPG, suggesting a tumor-suppressor-like role. The study’s findings could improve our understanding of T2R14 mechanisms and help develop strategies to advance oral cancer treatment by targeting T2R14. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors and Diseases)

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31 pages, 1115 KB

Open AccessReview

Peculiar Cat with Many Lives: PUMA in Viral Infections

by Zbigniew Wyżewski, Justyna Stępkowska, Pola Pruchniak, Adrianna Niedzielska, Karolina Paulina Gregorczyk-Zboroch and Matylda Barbara Mielcarska

Cells 2026, 15(3), 278; https://doi.org/10.3390/cells15030278 - 1 Feb 2026

Abstract

Apoptosis is a natural mechanism that shapes morphogenesis and helps maintain tissue homeostasis in healthy organisms. It is also extensively studied in the context of pathologies such as cancer and viral infections. The course of the latter strictly depends on host cell viability; [...] Read more.

Apoptosis is a natural mechanism that shapes morphogenesis and helps maintain tissue homeostasis in healthy organisms. It is also extensively studied in the context of pathologies such as cancer and viral infections. The course of the latter strictly depends on host cell viability; therefore, regulators of apoptosis may play essential roles in distinct viral infections as well as virus-dependent diseases. The p53-upregulated modulator of apoptosis (PUMA), a pro-apoptotic member of the B-cell lymphoma 2 (Bcl-2) family, directly disrupts mitochondrial integrity, thereby promoting the intrinsic apoptotic pathway. PUMA-mediated cell death act as a double-edged sword that may either facilitate viral infection and its consequences or counteract them, depending on the infectious agent and the complex context of pathogen–host interactions. Accordingly, various viruses have evolved strategies to modulate host cell viability to their advantage by targeting PUMA—either by suppressing transcription of the PUMA gene, binding and inactivating the PUMA protein, or, conversely, inducing its production. In this work, we describe the role of PUMA in infections caused by distinct viruses and in associated diseases, viral strategies for modulating PUMA-related signaling pathways, and potential therapeutic implications. Full article

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