Cells

22 pages, 3452 KB

Open AccessArticle

Engineering Bi-Specific CAR-NK Cells to Restore Antibody-Dependent Cellular Cytotoxicity in Solid Tumors

by Jee Young Chung, Jung Eun Kim, Daseuri Cha, Hye Jin Lee, Els Verhoeyen, Hee Jung An and Jung Eun Park

Cells 2026, 15(4), 373; https://doi.org/10.3390/cells15040373 - 20 Feb 2026

Abstract

Natural Killer (NK) cell-based immunotherapy relies on CD16-mediated Antibody-Dependent Cellular Cytotoxicity (ADCC), yet the ovarian tumor microenvironment (TME) severely compromises this function via Transforming Growth Factor-beta (TGF-β). This study investigated the molecular mechanisms driving this suppression and evaluated a bi-specific Chimeric Antigen Receptor [...] Read more.

Natural Killer (NK) cell-based immunotherapy relies on CD16-mediated Antibody-Dependent Cellular Cytotoxicity (ADCC), yet the ovarian tumor microenvironment (TME) severely compromises this function via Transforming Growth Factor-beta (TGF-β). This study investigated the molecular mechanisms driving this suppression and evaluated a bi-specific Chimeric Antigen Receptor (CAR) strategy to overcome this hurdle. Primary PBNK cells exposed to TGF-β showed sustained canonical SMAD2 phosphorylation, accompanied by a marked reduction in activating receptors such as CD16 and NKG2D and an increase in exhaustion markers such as PD-1. Functionally, these phenotypic alterations led to failed infiltration and cytotoxicity in vitro and within ovarian cancer-derived spheroids. To overcome this limitation, we engineered NK-92 cells with a bi-specific CAR-targeting Folate Receptor Alpha (FRα) and CD16. While TGF-β typically impairs NK cell function, our armed CAR-NK cells successfully infiltrated tumoroids and synergized with Trastuzumab to induce potent ADCC-mediated lysis. Our findings define the TGF-β/SMAD2 axis as a central driver of NK cell dysfunction in ovarian cancer and demonstrate that bi-specific CAR-NK platforms offer a robust therapeutic solution to bypass TME-induced suppression and restore antibody-mediated tumor suppression. Full article

(This article belongs to the Section Cell and Gene Therapy)

► Show Figures

Figure 1

30 pages, 1046 KB

Open AccessReview

Mitochondria at the Crossroads of Cardiovascular Disease: Mechanistic Drivers and Emerging Therapeutic Strategies

by Sonila Alia, Gaia Pedriali, Paolo Compagnucci, Yari Valeri, Valentina Membrino, Tiziana Di Crescenzo, Elena Tremoli, Laura Mazzanti, Arianna Vignini, Paolo Pinton and Michela Casella

Cells 2026, 15(4), 372; https://doi.org/10.3390/cells15040372 - 20 Feb 2026

Abstract

Mitochondria are central regulators of cardiac homeostasis, integrating energy production, redox balance, calcium handling, and innate immune signaling. In cardiovascular disease (CVD), mitochondrial dysfunction acts as a unifying mechanism connecting oxidative stress, metabolic inflexibility, inflammation, and structural remodeling. Disturbances in mitochondrial quality control—encompassing [...] Read more.

Mitochondria are central regulators of cardiac homeostasis, integrating energy production, redox balance, calcium handling, and innate immune signaling. In cardiovascular disease (CVD), mitochondrial dysfunction acts as a unifying mechanism connecting oxidative stress, metabolic inflexibility, inflammation, and structural remodeling. Disturbances in mitochondrial quality control—encompassing fusion–fission dynamics, PINK1/Parkin- and receptor-mediated mitophagy, biogenesis, and proteostasis—compromise mitochondrial integrity and amplify cardiomyocyte injury. Excess reactive oxygen species, mitochondrial DNA release, and calcium overload further activate cGAS–STING, NLRP3 inflammasomes, and mPTP-driven cell death pathways, perpetuating maladaptive remodeling. Therapeutic strategies targeting mitochondrial dysfunction have rapidly expanded, ranging from mitochondria-targeted antioxidants (such as MitoQ and SS-31), nutraceuticals, metabolic modulators (SGLT2 inhibitors, metformin), and mitophagy or biogenesis activators to innovative approaches including mtDNA editing, nanocarrier-based delivery, and mitochondrial transplantation. These interventions aim to restore organelle structure, improve bioenergetics, and reestablish balanced quality control networks. This review integrates recent mechanistic insights with emerging translational evidence, outlining how mitochondria function as bioenergetic and inflammatory hubs in CVD. By synthesizing established and next-generation therapeutic strategies, it highlights the potential of precision mitochondrial medicine to reshape the future management of cardiovascular disease. Full article

16 pages, 1406 KB

Open AccessReview

The Effects of Microgravity on Differentiation and Regeneration in Neural Stem Cells

by Qiuyan Hao, Hao Tian, Na Lv, Fengtang Yang, Hui Zhen and Zhonghong Cao

Cells 2026, 15(4), 371; https://doi.org/10.3390/cells15040371 - 20 Feb 2026

Abstract

Neural stem cells (NSCs) are self-renewing, multipotent cells of the central nervous system (CNS) that can differentiate into a range of specialized cell types, including neurons, astrocytes, and oligodendrocytes (OLs). Due to their remarkable ability to self-renew and differentiate, NSCs hold immense potential [...] Read more.

Neural stem cells (NSCs) are self-renewing, multipotent cells of the central nervous system (CNS) that can differentiate into a range of specialized cell types, including neurons, astrocytes, and oligodendrocytes (OLs). Due to their remarkable ability to self-renew and differentiate, NSCs hold immense potential for the treatment of neurodegenerative diseases (NDDs). However, clinical translation remains hindered by challenges such as expansion difficulties and phenotypic drift. This review synthesizes evidence on the divergent effects of microgravity on NSC biology. While real spaceflight has been shown to enhance NSC proliferation, it paradoxically reduces neurosphere volume. Microgravity simulations yield contrasting results: rotating wall vessel (RWV) systems promote neuron and astrocyte generation, whereas rotating cell culture systems (RCCSs) inhibit differentiation despite the use of pro-differentiation media. These phenotypic variations critically depend on experimental conditions, cell sources, and observation time. Future research should focus on elucidating cross-pathway interactions and optimizing culture parameters to enable clinical-scale NSC applications. Full article

► Show Figures

Figure 1

10 pages, 618 KB

Open AccessReview

Beyond Ion Channels: Emerging Roles of FGF12 in Cellular Regulation and Cancer Progression

by Zechao Huang and Xuesen Dong

Cells 2026, 15(4), 370; https://doi.org/10.3390/cells15040370 - 19 Feb 2026

Abstract

Fibroblast growth factor 12 (FGF12), a member of the intracellular fibroblast growth factor homologous factor (iFGF) subfamily, has been widely studied for its role in the modulation of voltage-gated ion channels. However, recent studies suggest that FGF12 possesses various cellular functions beyond ion [...] Read more.

Fibroblast growth factor 12 (FGF12), a member of the intracellular fibroblast growth factor homologous factor (iFGF) subfamily, has been widely studied for its role in the modulation of voltage-gated ion channels. However, recent studies suggest that FGF12 possesses various cellular functions beyond ion channel regulation, particularly in cancer progression. Accumulating evidence indicates that the upregulation of FGF12 is associated with tumor survival, therapeutic resistance, and poor prognosis through signaling pathways independent of its canonical ion channel interactions. This review summarizes the current understanding of FGF12’s non-canonical functions, highlights its emerging roles in cellular regulation, and discusses its potential mechanism in oncogenic progression. Understanding these novel functions may provide a new aspect for therapeutic targeting of FGF12 in malignancies. Full article

► Show Figures

Figure 1

38 pages, 970 KB

Open AccessReview

Ion Channel Integration and Functional Coupling in Salivary Gland Fluid Secretion

by Tarek Mohamed Abd El-Aziz and Brij B. Singh

Cells 2026, 15(4), 369; https://doi.org/10.3390/cells15040369 - 19 Feb 2026

Abstract

Salivary glands produce saliva through precisely coordinated epithelial ion transport processes. Ion channels are essential components of the molecular machinery that convert neural and hormonal signals into targeted ion and water flux. This review focuses on the integrated molecular and cellular mechanisms by [...] Read more.

Salivary glands produce saliva through precisely coordinated epithelial ion transport processes. Ion channels are essential components of the molecular machinery that convert neural and hormonal signals into targeted ion and water flux. This review focuses on the integrated molecular and cellular mechanisms by which ion channels cooperate to generate salivary fluid under physiological conditions. Saliva formation proceeds through two sequential stages: isotonic primary fluid secretion by acinar cells, followed by ionic modification within the ductal epithelium. Parasympathetic stimulation activates muscarinic M1/3 receptors, initiating intracellular calcium signaling through inositol 1,4,5-trisphosphate-dependent release from the endoplasmic reticulum and sustained calcium entry via Orai1/TRPC channels. Elevated cytosolic calcium activates apical ANO1/TMEM16A chloride channels, the rate-limiting step in acinar fluid secretion, together with basolateral calcium-activated potassium channels that preserve the electrochemical driving force for chloride efflux. Chloride accumulation is maintained by Na⁺/K⁺-ATPase and the Na⁺-K⁺-2Cl⁻ cotransporter, while osmotic gradients drive water movement through apical aquaporin-5 and basolateral aquaporin-1/3. As primary saliva traverses the ductal system, epithelial sodium channels, CFTR, and additional ion transport pathways reabsorb sodium and chloride and secrete potassium and bicarbonate, producing hypotonic final saliva. By synthesizing calcium signaling, chloride and potassium conductance, sodium handling, and epithelial polarity into a unified framework, this review establishes ion channel integration as the fundamental basis of salivary gland fluid secretion. Full article

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

► Show Figures

Figure 1

13 pages, 1012 KB

Open AccessReview

From Cell Lines to Avatars: Charting the Future of Preclinical Modeling in T-Cell Malignancies

by Pier Paolo Piccaluga, Luigi Cimmino, Valeriia Tsekhovska, Pietro Cimatti, Claudia Innocenti, Sabrina Seidenari, Giulia Calafato, Floriana J. Di Paola and Giovanni Tallini

Cells 2026, 15(4), 368; https://doi.org/10.3390/cells15040368 - 19 Feb 2026

Abstract

T-cell malignancies represent a complex spectrum of clinically and biologically heterogeneous diseases. Effective translational research and drug development are critically dependent on preclinical models that faithfully recapitulate this diversity. This review analyzes the current preclinical landscape, identifying a profound disparity between the clinical [...] Read more.

T-cell malignancies represent a complex spectrum of clinically and biologically heterogeneous diseases. Effective translational research and drug development are critically dependent on preclinical models that faithfully recapitulate this diversity. This review analyzes the current preclinical landscape, identifying a profound disparity between the clinical spectrum of T-cell neoplasms and the available in vitro tools. We demonstrate that the existing armamentarium of cell lines is heavily skewed, with an abundance of models for T-cell lymphoblastic leukemia/lymphoma (T-ALL), cutaneous T-cell lymphoma (CTCL), and anaplastic large cell lymphoma (ALCL). This skew is a direct result of a biological selection bias, as these entities are often driven by potent, TME-independent oncogenes (e.g., NOTCH1 mutations, NPM1-ALK fusions) conducive to immortalization. Conversely, the majority of peripheral T-cell lymphoma (PTCL) subtypes, which are frequently TME-dependent and clinically aggressive, remain “preclinical orphans” with few or no authenticated models. This “preclinical void” constitutes a major bottleneck, impeding mechanistic studies and therapeutic progress. We discuss the limitations of 2D cultures and highlight the necessity of adopting advanced platforms, such as patient-derived xenografts (PDX) and 3D organoid systems. These “avatar” models preserve vital tumor heterogeneity and microenvironmental context, offering superior predictive value. The systematic development and integration of these next-generation models are essential to bridge the translational gap and advance precision medicine for all patients with T-cell malignancies. Full article

(This article belongs to the Special Issue Hematopoietic Cell Lines as Models for Leukemia and Lymphoma)

► Show Figures

Figure 1

17 pages, 3914 KB

Open AccessArticle

Plasma Extracellular Vesicles from Bronchopulmonary Dysplasia Infants Initiate Inflammation and Abnormal Angiogenesis in Neonatal Murine Retinas

by Huijun Yuan, Matthew R. Duncan, Shaoyi Chen, Merline Benny, Augusto Schmidt, Karen Young, Audina M. Berrocal, M. Elizabeth Hartnett and Shu Wu

Cells 2026, 15(4), 367; https://doi.org/10.3390/cells15040367 - 19 Feb 2026

Abstract

Purpose: To investigate the mechanisms by which plasma extracellular vesicles (EVs) from preterm infants with bronchopulmonary dysplasia (BPD) elicit inflammation and abnormal angiogenesis in neonatal mouse retinas. Methods: EVs from the plasma of 7-day-old preterm infants, born between 23^0/7 and 29^6/7 [...] Read more.

Purpose: To investigate the mechanisms by which plasma extracellular vesicles (EVs) from preterm infants with bronchopulmonary dysplasia (BPD) elicit inflammation and abnormal angiogenesis in neonatal mouse retinas. Methods: EVs from the plasma of 7-day-old preterm infants, born between 23^0/7 and 29^6/7 weeks of gestation, with BPD or without BPD (nBPD) at 36 weeks postmenstrual ages, were adoptively transferred into postnatal day 3 (P3) mice via intravenous retro-orbital sinus injection. Inflammation and pathological neovascularization in neonatal mouse retinas were examined by immunohistochemistry of retinal flat mounts for Allograft Inflammatory Factor 1 (AIF1), CD206, or Glial Fibrillary Acidic Protein (GFAP) and isolectin-B4 (IB4) staining on P17. Retinal inflammation-related transcripts were assessed by qRT-PCR. Proteomic profiles of BPD and nBPD EVs were examined by Liquid Chromatograph Mass Spectrometer/Mass Spectrometer (LC-MS/MS) and Gene Set Enrichment Analysis (GSEA). Results: Adoptively transferred EVs from BPD and nBPD infants crossed the blood–retinal barrier (BRB) in recipient mouse pups. BPD-EVs increased retinal activated microglia, Müller cells, and twisted proliferative neovascularization compared to nBPD-EVs. BPD-EVs also elevated retinal transcripts regulating inflammation and angiogenesis, including NOD-, LRR- and pyrin domain-containing protein 3 (Nlrp3), Apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc), Caspase 3 (Casp3), Caspase 8 (Casp8), Gasdermin D (Gsdmd), Il1β, Il6, Aif1, and Vascular endothelial growth factor (Vegf). Proteomics analysis revealed that BPD-EVs had significantly elevated levels of inflammation and angiogenesis-related proteins compared to nBPD-EVs. Conclusions: BPD-EVs promote inflammation and abnormal neovascularization by upregulating genes related to apoptosis and inflammation in neonatal mouse retinas. EV protein profiles suggest that elevated levels of proteins such as Defensin alpha 1B (DEFA1B), Insulin-like growth factor binding protein 2 (IGFBP2), CD5 antigen-like (CD5L), von Willebrand factor (vWF), and Tenascin C (TNC) in BPD-EVs may contribute to the observed inflammation and angiogenesis. Full article

(This article belongs to the Section Cell Microenvironment)

► Show Figures

Figure 1

34 pages, 1286 KB

Open AccessReview

Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences

by Gabriella Schiera, Giulia Macajone, Sara Volpes, Laura Greco, Carlo Maria Di Liegro, Graziella Serio, Fabio Caradonna and Flores Naselli

Cells 2026, 15(4), 366; https://doi.org/10.3390/cells15040366 - 18 Feb 2026

Abstract

Maternal nutrition during pregnancy critically influences fetal programming, shaping the offspring’s lifelong health and disease susceptibility. Both undernutrition and overnutrition affect fetal metabolism, predisposing offspring to obesity and cardiometabolic disorders in adulthood. This review examines current evidence on how maternal nutrition, particularly overnutrition [...] Read more.

Maternal nutrition during pregnancy critically influences fetal programming, shaping the offspring’s lifelong health and disease susceptibility. Both undernutrition and overnutrition affect fetal metabolism, predisposing offspring to obesity and cardiometabolic disorders in adulthood. This review examines current evidence on how maternal nutrition, particularly overnutrition and its complications, such as gestational diabetes mellitus (GDM) and obesity, affects offspring health. It also explores the biochemical and epigenetic mechanisms underlying aberrant fetal programming induced by an unfavorable intrauterine environment. Excess nutrient exposure in utero alters fetal metabolic pathways by modifying the expression of key metabolic genes and nutrient sensors, increasing susceptibility to metabolic syndrome later in life. Maternal obesity has additionally been linked to cognitive dysfunction, immune alterations, and elevated cancer-related mortality in the offspring. GDM exposure disrupts fetal hypothalamic development, impairing appetite regulation. Emerging evidence suggests that epigenetic changes induced by maternal overnutrition may be transmitted across generations and that paternal obesity may also contribute to fetal metabolic programming. Although lifestyle interventions during pregnancy have been tested, they show limited long-term benefits, whereas pre-pregnancy BMI remains the strongest predictor of offspring obesity, emphasizing the critical role of preconception care and the prevention of overweight in women of reproductive age. Full article

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

23 pages, 1552 KB

Open AccessReview

Translating Gastric Cancer Genomics into Targeted Therapy: Mechanistic Insights from Animal Models and Patient-Derived Systems

by Rong-Yaun Shyu, Lu-Kai Wang and Fu-Ming Tsai

Cells 2026, 15(4), 365; https://doi.org/10.3390/cells15040365 - 18 Feb 2026

Abstract

Gastric cancer remains a leading cause of cancer-related mortality worldwide and is marked by pronounced molecular heterogeneity. Advances in genomic profiling have identified key genetic alterations, including oncogenes (HER2, PIK3CA, and MYC), tumor suppressor genes (TP53, CDH1 [...] Read more.

Gastric cancer remains a leading cause of cancer-related mortality worldwide and is marked by pronounced molecular heterogeneity. Advances in genomic profiling have identified key genetic alterations, including oncogenes (HER2, PIK3CA, and MYC), tumor suppressor genes (TP53, CDH1, and ARID1A), and regulators of genome stability and cell architecture (MLH1, RHOA, and CLDN18), which have driven the development of targeted therapeutic strategies. Although genetically engineered mouse models and xenograft systems have been indispensable for functional validation and preclinical drug testing, many approaches that showed promising efficacy in animal models—such as inhibition of EGFR, MET, FGFR2, and the PI3K pathway—failed to translate into overall survival benefits in clinical trials, highlighting major translational limitations. In contrast, HER2- and CLDN18.2-targeted therapies represent rare but notable clinical successes, underscoring the importance of true oncogenic dependency, precise biomarker-driven patient selection, and robust preclinical validation. In this review, we systematically categorize gastric cancer-associated genes according to their biological functions, summarize representative animal models, and critically examine key successes and failures in clinical translation, emphasizing the need for biologically faithful models and precision-driven translational strategies. Full article

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

► Show Figures

Figure 1

30 pages, 852 KB

Open AccessReview

Exploring the Impact of Polychlorinated Biphenyls (PCBs) on the Development of MASLD: A Comprehensive Review

by Valeria Longo, Giuseppa Augello, Noemi Aloi, Alessandra Cusimano, Anna Licata, Emanuele Cannizzaro, Melchiorre Cervello, Maurizio Soresi, Paolo Colombo and Lydia Giannitrapani

Cells 2026, 15(4), 364; https://doi.org/10.3390/cells15040364 - 18 Feb 2026

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is becoming the most common liver disease, affecting between 30 and 40% of the global population. MASLD is a multifaceted disease spectrum that is closely associated with obesity, insulin [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is becoming the most common liver disease, affecting between 30 and 40% of the global population. MASLD is a multifaceted disease spectrum that is closely associated with obesity, insulin resistance, type 2 diabetes mellitus and, more broadly, metabolic syndrome. All these conditions increase the risk of liver-related mortality, which explains the intense research efforts in recent years to better elucidate its pathogenesis. The crucial impact of environmental pollutants on the development of MASLD is now well recognized. Polychlorinated biphenyls (PCBs) are environmental contaminants that act as endocrine disruptors. Recently, they have been associated with the development of diabetes, obesity, MASLD, and cancer. The association between liver diseases, namely toxicant-associated steatotic liver disease and steatohepatitis (TASLD and TASH, respectively), and occupational exposure to PCBs and other industrial chemicals has been documented by several lines of evidence, whereas the potential role of low-level environmental pollution in liver disease and in MASLD remains incompletely understood. Previous studies on animal models have shown that PCB exposure is associated with steatosis/steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma (HCC), altered liver enzymes, and mortality in exposed populations. This review investigates the mechanisms underlying hepatic steatogenesis in preclinical and animal models and analyzes the existing literature on the possible role of PCBs, together with the other conventional risk factors, in the development of MASLD in humans. Full article

(This article belongs to the Special Issue New Molecular Insights into Hepatitis and Hepatic Cancer)

► Show Figures

Graphical abstract

21 pages, 926 KB

Open AccessReview

GSCs in the Transdifferentiation Phenomenon: Focus on CAR-T-Based Therapy

by Martina Di Marco, Alessandro Lo Giudice, Francesca Chiara Cecala, Sabrina David, Celeste Caruso Bavisotto, Claudia Campanella, Alessandra Maria Vitale and Giuseppa D’Amico

Cells 2026, 15(4), 363; https://doi.org/10.3390/cells15040363 - 18 Feb 2026

Abstract

Glioblastoma (GBM) remains one of the most lethal brain tumors, largely due to the resilience and plasticity of glioblastoma stem cells (GSCs), which drive tumor growth, recurrence, and resistance to conventional therapies. A key mechanism underlying their aggressiveness is transdifferentiation, whereby GSCs acquire [...] Read more.

Glioblastoma (GBM) remains one of the most lethal brain tumors, largely due to the resilience and plasticity of glioblastoma stem cells (GSCs), which drive tumor growth, recurrence, and resistance to conventional therapies. A key mechanism underlying their aggressiveness is transdifferentiation, whereby GSCs acquire endothelial- and pericyte-like phenotypes, promoting neovascularization and remodeling the tumor microenvironment to sustain malignancy. Conventional treatments often fail to eliminate these resilient populations, highlighting the need for innovative targeted strategies. Chimeric antigen receptor (CAR)-based immunotherapies offer a targeted strategy to specifically eliminate GSCs and interfere with their role in promoting tumor vascularization and suppressing immune responses. This review aims to provide a comprehensive overview of the molecular mechanisms driving GSC transdifferentiation and to summarize the current landscape of CAR-T therapies developed to target these cells. By integrating knowledge of GSC biology with advances in CAR-T-based interventions, this work highlights the potential of next-generation immunotherapies to overcome therapeutic resistance, limit tumor recurrence, and improve clinical outcomes in GBM. Full article

(This article belongs to the Special Issue Neuro-Oncological Advances in Stem Cell Research: A New Era in Brain Tumor Therapy)

► Show Figures

Figure 1

48 pages, 3575 KB

Open AccessReview

Targeting Glycolytic Metabolism in Cancer Therapy: Current Approaches and Future Perspectives

by Shuang Li, Jie Gong, Baorong Kang, Zelong Wang, Yuxuan Ma, Xinhua Xia and Hong Yan

Cells 2026, 15(4), 362; https://doi.org/10.3390/cells15040362 - 18 Feb 2026

Abstract

Targeting the Warburg effect (aerobic glycolysis) in tumor cells represents a promising metabolic therapeutic strategy in cancer research. This review analyzes the regulatory mechanisms and therapeutic potential of key glycolysis pathway components, including glucose transporters (GLUTs) and glycolytic enzymes such as hexokinase 2 [...] Read more.

Targeting the Warburg effect (aerobic glycolysis) in tumor cells represents a promising metabolic therapeutic strategy in cancer research. This review analyzes the regulatory mechanisms and therapeutic potential of key glycolysis pathway components, including glucose transporters (GLUTs) and glycolytic enzymes such as hexokinase 2 (HK2), phosphofructokinase (PFK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA). We evaluate the molecular mechanisms of various inhibitors and the current clinical development landscape, noting that limitations of monotherapy stem not only from tumor metabolic plasticity but also largely from the unacceptable toxicity of many inhibitors due to the essential role of glycolysis in normal cell metabolism. Furthermore, we explore the molecular basis of synergistic interactions between glycolysis inhibitors and chemotherapy, radiotherapy, immunotherapy, photothermal therapy, and targeted therapy, proposing that rational combination strategies may help overcome resistance and improve therapeutic efficacy. Finally, the review outlines future challenges and directions, emphasizing that the primary obstacle in metabolic treatments is achieving selective inhibition of glycolytic enzymes in cancer cells while sparing normal cells. To address this challenge, the development of high-selectivity agents, cancer-specific nanodelivery systems, precise biomarker identification, and innovative combination regimens based on metabolic-immune regulation is crucial for advancing glycolysis-targeted therapy toward clinical translation. Full article

(This article belongs to the Section Cellular Metabolism)

15 pages, 2392 KB

Open AccessArticle

Upregulation of the lncRNA MEG3 in Metastatic Hepatoblastoma

by Morgan L. Brown, Maryam G. Shaikh, Nazia Nazam, Ali M. Eakes, Pranava Nande, Abdulraheem Kaimari, Joel C. Opara, Jamie M. Aye, Karina J. Yoon and Elizabeth A. Beierle

Cells 2026, 15(4), 361; https://doi.org/10.3390/cells15040361 - 18 Feb 2026

Abstract

Hepatoblastoma is the predominant primary liver malignancy in children, and outcomes remain poor for patients with metastatic disease. Long non-coding RNAs (lncRNAs) regulate tumor behavior, but their role in metastatic hepatoblastoma is not well defined. This study investigates the expression and functional significance [...] Read more.

Hepatoblastoma is the predominant primary liver malignancy in children, and outcomes remain poor for patients with metastatic disease. Long non-coding RNAs (lncRNAs) regulate tumor behavior, but their role in metastatic hepatoblastoma is not well defined. This study investigates the expression and functional significance of the lncRNA, maternally expressed gene 3 (MEG3), in a metastatic hepatoblastoma model. RNA sequencing comparing the metastatic hepatoblastoma cell line, HLM_2, with its parental HuH6 cell line identified MEG3 as being significantly upregulated in metastatic cells. MEG3 expression was examined using hepatoblastoma patient datasets and validated using qPCR in cell lines, orthotopic tumors, and COA67 patient-derived xenografts. The effects of siRNA MEG3 knockdown in HLM_2 cells on clonogenicity, migration, and invasion were evaluated. The effects of MEG3 overexpression on migration and invasion were assessed in HuH6 cells. MEG3 was significantly upregulated in metastatic cells and orthotopic tumors compared with controls. MEG3 silencing reduced clonogenicity, tumorsphere formation, migration, and invasion. MEG3 overexpression increased migration and invasion. These findings indicate that MEG3 contributes to an aggressive tumor phenotype, highlighting the need for further examination into its mechanistic role in hepatoblastoma and its potential as a biomarker or therapeutic target. Full article

(This article belongs to the Special Issue Pediatric Liver Tumors: Molecular Mechanisms and Therapeutic Strategies)

► Show Figures

Figure 1

19 pages, 1643 KB

Open AccessArticle

Stefin B and Cystatin C Deficiency Suppresses Tumor Growth and Alters Tumor Microenvironment in a Breast Cancer Model

by Petra Matjan Štefin, Janja Završnik, Miha Butinar, Georgy Mikhaylov, Boris Turk and Olga Vasiljeva

Cells 2026, 15(4), 360; https://doi.org/10.3390/cells15040360 - 17 Feb 2026

Abstract

Background/Objectives: Cysteine cathepsins and their endogenous inhibitors have been shown to possess context-dependent functions in cancer progression, including the regulation of tumor metabolic pathways. Stefin B and cystatin C, intracellular and extracellular protease inhibitors, respectively, can modulate tumor biology through protease-dependent and [...] Read more.

Background/Objectives: Cysteine cathepsins and their endogenous inhibitors have been shown to possess context-dependent functions in cancer progression, including the regulation of tumor metabolic pathways. Stefin B and cystatin C, intracellular and extracellular protease inhibitors, respectively, can modulate tumor biology through protease-dependent and protease-independent mechanisms. This study investigated their combined functions and potential roles as tumor promoters in breast cancer in a spontaneous breast cancer mouse model (PyMT mice). Methods: We generated PyMT transgenic mice lacking both stefin B and cystatin C (double-knockout, DKO) and compared their tumor growth kinetics, proliferation, apoptosis, and metastatic burden with those of wild-type control mice. Immunohistochemistry was performed to characterize tumor macrophage infiltration and polarization. Results: DKO mice demonstrated delayed tumor onset, significantly slower tumor growth, reduced proliferation, increased apoptosis, and fewer lung metastases compared to wild-type controls. Immunohistochemistry revealed enhanced macrophage infiltration of the tumors, accompanied by a pronounced shift toward antitumorigenic M1 (CD86⁺) polarization, while M2 (CD206⁺) populations remained unchanged, indicating an immunological reprogramming of the tumor microenvironment toward a pro-inflammatory, tumor-suppressive state. Conclusions: Our results demonstrated a potential function of stefin B and cystatin C as tumor promoters in breast cancer through complementary mechanisms. Simultaneous depletion of both inhibitors revealed synergistic effects and remodeled the immune microenvironment to favor tumor suppression. These results suggest previously unknown roles for stefin B and cystatin C in tumor development and progression, which encourage further investigation of the cancer metabolic mechanisms underlying tumor behavior and their dynamic interplay with the microenvironment. Full article

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

► Show Figures

Graphical abstract

19 pages, 7185 KB

Open AccessArticle

Wnt5a Regulates Embryonic Müllerian Duct Development Through the Non-Canonical Wnt PCP Pathway

by Isaac Kyei-Barffour, Sarah Williams, Bhawna Kushawaha and Emanuele Pelosi

Cells 2026, 15(4), 359; https://doi.org/10.3390/cells15040359 - 17 Feb 2026

Abstract

Müllerian anomalies are anatomical variations of the female reproductive tract resulting from the incomplete development of the embryonic Müllerian ducts. The molecular mechanisms driving Müllerian duct development are complex and poorly understood, resulting in the largely unexplained aetiology of these conditions. WNT5A is [...] Read more.

Müllerian anomalies are anatomical variations of the female reproductive tract resulting from the incomplete development of the embryonic Müllerian ducts. The molecular mechanisms driving Müllerian duct development are complex and poorly understood, resulting in the largely unexplained aetiology of these conditions. WNT5A is a critical regulator of key developmental processes, including patterning, cell proliferation, and migration. Mutations of WNT5A have been associated with Robinow syndrome, a congenital condition characterized by skeletal and genital anomalies. In the mouse, WNT5A is necessary for the posterior development of the Müllerian duct, and ablation of Wnt5a results in vaginal agenesis. However, Wnt5a-/- uterine horns are hypoplastic and over 60% shorter than the wild type, suggesting specific functions in anterior Müllerian duct development. To better understand the role of Wnt5a, we performed single-cell RNA sequencing of developing Müllerian ducts. We found that the non-canonical Wnt PCP pathway was dysregulated in Wnt5a-/- mice. In addition, Wnt5a-/- Müllerian ducts were enriched in oviductal mesenchymal cells due to the transformation of the anterior uterine horns into oviducts. Our results indicate additional roles for Wnt5a during Müllerian duct development, prompting further investigations into uterine functions and anatomy in complex clinical cases of Müllerian anomalies including Robinow syndrome. Full article

► Show Figures

Figure 1

16 pages, 5303 KB

Open AccessArticle

Metabolic Syndrome Predisposes Ossabaw Minipig Retina to an Early Neurodegenerative Milieu

by Scholastica Go, Rayne R. Lim, Anju E. Thomas, Paras K. Mishra and Shyam S. Chaurasia

Cells 2026, 15(4), 358; https://doi.org/10.3390/cells15040358 - 17 Feb 2026

Abstract

The miniature (mini) Ossabaw pigs are proposed as a translational preclinical model for testing and developing novel therapeutics for human diseases, including cystic fibrosis, cancer, and metabolic syndrome (MetS). In recent years, pigs have gained similar attention for studying retinal abnormalities and disorders [...] Read more.

The miniature (mini) Ossabaw pigs are proposed as a translational preclinical model for testing and developing novel therapeutics for human diseases, including cystic fibrosis, cancer, and metabolic syndrome (MetS). In recent years, pigs have gained similar attention for studying retinal abnormalities and disorders owing to their close resemblance in size, anatomy, vasculature, and pathology to the human eye compared with their rodent counterparts. In our previous study, Ossabaw minipigs fed a Western diet for 10 weeks and followed for 3.5 months exhibited early signs of retinal degeneration and vascular abnormalities, mimicking the early stages of diabetic retinopathy (DR). To further evaluate pathomorphological alterations across neuronal and non-neuronal cell types, the present study comprehensively investigated individual retinal layers using cell-type-specific immunostaining. We found that the Western diet-fed mini pigs had reduced rhodopsin and blue opsins, changes in bipolar and ganglion cells, and reduced density of pre- and post-synaptic connections. Moreover, the retinas of obese mini pigs showed evidence of gliosis and microglial activation. Our findings suggest that a Western diet-induced metabolic disorder exhibits an early neurodegenerative milieu and further demonstrate the suitability of Ossabaw mini pigs as a model for human retinal diseases associated with MetS, such as DR and diabetic macular edema (DME). Full article

(This article belongs to the Special Issue Advances in the Discovery of Retinal Degeneration)

► Show Figures

Figure 1

18 pages, 8258 KB

Open AccessArticle

Regulation of Mitochondrial Biogenesis in Diabetic Retinopathy

by Jay Kumar and Renu A. Kowluru

Cells 2026, 15(4), 357; https://doi.org/10.3390/cells15040357 - 17 Feb 2026

Abstract

Mitochondrial dysfunction plays a major role in diabetic retinopathy development and in its resistance to halt after the reversal of hyperglycemia (metabolic memory). Diabetes also upregulates many long noncoding RNAs, RNAs with >200 nucleotides with no reading frame, and several of them resist [...] Read more.

Mitochondrial dysfunction plays a major role in diabetic retinopathy development and in its resistance to halt after the reversal of hyperglycemia (metabolic memory). Diabetes also upregulates many long noncoding RNAs, RNAs with >200 nucleotides with no reading frame, and several of them resist reversal after hyperglycemia cessation. Our aim was to investigate the role of LncRNA HOTAIR, a master regulator of chromatin dynamics, in mitochondrial biogenesis in diabetic retinopathy and in metabolic memory. Using retinal endothelial cells and Müller cells, incubated in high glucose (20 mM D-glucose), the effect of HOTAIR-siRNA on mitochondrial biogenesis was investigated by quantifying mitochondrial mass, copy numbers, and mtDNA replication, structure, and function. HOTAIR’s role in metabolic memory was investigated by analyzing mitochondrial biogenesis in HOTAIR-siRNA transfected cells incubated in high glucose for four days, followed by normal glucose (5 mM D-glucose) for four days. HOTAIR was upregulated in both retinal vascular and nonvascular cells, and HOTAIR-siRNA ameliorated decreases in mtDNA biogenesis and protected their mitochondria from structural/functional damage. Reversal of high glucose insult failed to ameliorate HOTAIR upregulation and impaired mtDNA biogenesis in both endothelial and Müller cells, but regulation of HOTAIR during high glucose incubation, which followed normal glucose, prevented a decrease in mitochondrial mass and mtDNA copies. Thus, HOTAIR has a major role in mitochondrial biogenesis and in the continued impaired biogenesis in both vascular and nonvascular cells. Regulating HOTAIR may provide a therapeutic option to inhibit the development/progression of diabetic retinopathy. Full article

(This article belongs to the Special Issue Role of RNA as Regulator, Therapeutic Target and Probe for Early Disease Diagnosis)

15 pages, 629 KB

Open AccessReview

Comprehensive Review of Antiphospholipid Syndrome: Over Four Decades of Advances and Challenges

by Takao Koike

Cells 2026, 15(4), 356; https://doi.org/10.3390/cells15040356 - 17 Feb 2026

Abstract

Antiphospholipid syndrome (APS), first described in 1983, is a systemic autoimmune disorder characterized by recurrent arterial and venous thrombosis, pregnancy complications, and persistent antiphospholipid antibodies (aPL). Over four decades, significant advancements have been made in understanding APS pathogenesis, diagnostics, and treatment. Key discoveries [...] Read more.

Antiphospholipid syndrome (APS), first described in 1983, is a systemic autoimmune disorder characterized by recurrent arterial and venous thrombosis, pregnancy complications, and persistent antiphospholipid antibodies (aPL). Over four decades, significant advancements have been made in understanding APS pathogenesis, diagnostics, and treatment. Key discoveries include the development of standardized anticardiolipin antibody (aCL) assays, the identification of β2-glycoprotein I (β2GPI) as a critical cofactor, and the elucidation of the “two-hit” hypothesis, which explains thrombotic events through a combination of aPL-induced prothrombotic priming and secondary external triggers. Recent research has highlighted the roles of complement activation, neutrophil extracellular traps (NETs), and genetic predispositions shared with systemic lupus erythematosus (SLE). Innovations like the antiphospholipid score (aPL-S) and updated classification criteria, including the 2023 ACR/EULAR guidelines, have improved diagnostic precision and risk stratification. Despite these advances, challenges remain in assay standardization and addressing seronegative APS. Future directions emphasize the integration of multimodal biomarkers, precision diagnostics, and targeted therapies aimed at complement and NET pathways. These efforts aim to achieve individualized care, improving outcomes for APS patients through harmonized diagnostics, mechanistic therapeutics, and data-driven approaches. This review underscores the evolving understanding of APS and its potential for personalized management strategies. Full article

(This article belongs to the Special Issue Novel Autoantibodies in Systemic Autoimmune Diseases: Challenges and Perspectives)

► Show Figures

Figure 1

27 pages, 2009 KB

Open AccessArticle

Tumor-Derived LIF Promotes GDF15-Driven Cachexia and Adverse Outcomes in Gastric Cancer

by Cristina Di Giorgio, Nicola Natalizi, Maria Rosaria Sette, Martina Bordoni, Benedetta Sensini, Ginevra Lachi, Eleonora Giannelli, Francesca Paniconi, Luigi Cari, Silvia Marchianò, Michele Biagioli, Elva Morretta, Maria Chiara Monti, Bruno Charlier, Fabrizio Dal Piaz, Angela Zampella, Eleonora Distrutti, Luigina Graziosi, Annibale Donini and Stefano Fiorucci

Cells 2026, 15(4), 355; https://doi.org/10.3390/cells15040355 - 16 Feb 2026

Abstract

Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle and adipose tissue loss, systemic inflammation, and poor clinical outcomes, and represents a major unmet clinical need in gastric cancer. Growth Differentiation Factor 15 (GDF15) is a key mediator of cachexia-associated [...] Read more.

Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle and adipose tissue loss, systemic inflammation, and poor clinical outcomes, and represents a major unmet clinical need in gastric cancer. Growth Differentiation Factor 15 (GDF15) is a key mediator of cachexia-associated anorexia and tissue wasting; however, the upstream mechanisms regulating its expression in gastric cancer remain poorly defined. Leukemia Inhibitory Factor (LIF), a pleiotropic cytokine implicated in tumor progression and metabolic dysregulation, has emerged as a potential regulator of cachexia-related pathways. Here, we investigated the association between LIF in regulating GDF15 expression and its relationship with metabolic, inflammatory, and body composition alterations in gastric cancer. Transcriptomic profiling of paired neoplastic and non-neoplastic gastric mucosa from 61 gastric cancer patients revealed a significant upregulation of both LIF and GDF15 in tumor tissue, with a strong positive correlation between their expression levels. High GDF15 expression was associated with reduced overall survival, a finding validated in independent TCGA-STAD and ACRG cohorts. Intratumoral bile acid profiling uncovered a marked enrichment of primary bile acids and a depletion of secondary bile acids, resulting in reduced levels of bile acids with endogenous LIF receptor (LIFR) antagonist activity; elevated primary, LIFR non-antagonist bile acids were associated with worse survival outcomes. Clinically, increased LIF and GDF15 expression correlated with weight loss, heightened inflammatory burden, reduced serum protein and albumin levels, and impaired body composition in a sub-cohort of 19 patients. Notably, LIF expression showed a significant inverse association with both lumbar skeletal muscle index (L3SMI) and subcutaneous adipose tissue index (SATI). Mechanistically, experimental models demonstrated that LIF enhances proliferative activity in gastric cancer spheroids and exerts paracrine effects that impair myogenic differentiation and suppress hepatic metabolic gene expression. Collectively, these findings identify the LIF/GDF15 axis as a central driver of cancer-associated cachexia in gastric cancer and highlight LIF signaling as a potential therapeutic target. Full article

(This article belongs to the Special Issue Cellular Metabolism and Immune Regulation in Cancer Progression and Metastasis)

Journal Description

Cells

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI