Cells

15 pages, 3382 KB

Open AccessArticle

A Thiadiazolopyrimidinone-Based Molecule Targeting Annexin A6 Impairs Cell Motility and Epithelial-to-Mesenchymal Transition in Pancreatic Cancer Cells Lacking Annexin A1

by Raffaella Belvedere, Nunzia Novizio, Dafne Ruggiero, Mariangela Palazzo, Ines Bruno, Stefania Terracciano and Antonello Petrella

Cells 2026, 15(4), 386; https://doi.org/10.3390/cells15040386 - 23 Feb 2026

Viewed by 513

Abstract

Pancreatic carcinoma (PC) is the most lethal malignancy due to its aggressive behavior and limited therapeutic response. Among the annexin family, Annexin A1 (ANXA1) is documented to promote PC aggressiveness, and conversely, the role of Annexin A6 (ANXA6) is less explored. Here, we [...] Read more.

Pancreatic carcinoma (PC) is the most lethal malignancy due to its aggressive behavior and limited therapeutic response. Among the annexin family, Annexin A1 (ANXA1) is documented to promote PC aggressiveness, and conversely, the role of Annexin A6 (ANXA6) is less explored. Here, we report that ANXA6 is significantly upregulated in ANXA1 knockout (KO) MIA PaCa-2 cells. Using LAM20, our previously identified ANXA6 modulator, we show that inhibition of this protein impairs cell motility, and epithelial-to-mesenchymal transition markers, without affecting 2D/3D cell proliferation. ANXA6 siRNA-mediated knockdown reproduces LAM20 effects, suggesting a relationship with their impact on ANXA6. Interestingly, in ANXA1 KO cells, LAM20 reduced the migration/invasion rate differently from the ANXA1 inhibitor heparan sulfate, which retains effects on the wild-type (WT) MIA PaCa-2 counterpart. These findings suggest that in cells lacking ANXA1, ANXA6 plays a compensatory role in sustaining the aggressive phenotype, albeit to a lesser extent than in WT cells. Thus, LAM20 represents a promising therapeutic strategy to impair PC aggressiveness. Our study provides new insights into ANXA1/ANXA6 crosstalk and introduces a novel approach to disturb PC pro-invasive mechanisms. Targeting ANXA1 and ANXA6 is relevant because, where ANXA1 is downregulated/absent, ANXA6 expression can be restored in a compensatory manner, partially sustaining tumor progression. Full article

(This article belongs to the Special Issue Advances in Annexin Biology)

► Show Figures

Graphical abstract

15 pages, 5842 KB

Open AccessArticle

Impact of Plant Growth Regulators on Callus Induction in Cannabis sativa L.

by Margaux Thiry, Marcus Iken, Jenny Renaut, Stanley Lutts and Gea Guerriero

Cells 2026, 15(4), 385; https://doi.org/10.3390/cells15040385 - 23 Feb 2026

Viewed by 651

Abstract

Callogenesis is a fundamental step in plant biotechnology and tissue culture, providing the basis for multiple scientific and practical applications. In this study, the impact on callogenesis of different plant growth regulators was studied on Cannabis sativa L. (a non-commercial genotype of hemp), [...] Read more.

Callogenesis is a fundamental step in plant biotechnology and tissue culture, providing the basis for multiple scientific and practical applications. In this study, the impact on callogenesis of different plant growth regulators was studied on Cannabis sativa L. (a non-commercial genotype of hemp), with the objective of identifying the most suitable combination for the establishment of vigorously growing, friable calli. Forty-nine media combinations were evaluated using four PGRs: two auxins (2,4-dichlorophenoxyacetic acid, naphthaleneacetic acid) and two cytokinins (6-benzylaminopurine, kinetin). Parameters such as percentage of callus induction, proliferation, colour, texture, and growth area were assessed. Three media were identified for further spectrophotometric assays and targeted gene expression analysis: the first containing 2,4-dichlorophenoxyacetic acid 1.5 µM and benzylaminopurine 1.5 µM, the second with 2,4-dichlorophenoxyacetic acid 1.5 µM and kinetin 1.5 µM and the third supplemented with 2,4-dichlorophenoxyacetic acid 4.5 µM and kinetin 1.5 µM. The last medium proved to be superior in terms of vigour, friability and phenolic content and showed increased expression of genes involved in the early steps of the phenylpropanoid pathway. These findings highlight the central role of auxin–cytokinin interactions in regulating both callus formation and secondary metabolism. The optimised medium opens the way to subsequent biotechnological applications relying on the cultivation of plant cell suspension cultures. Full article

(This article belongs to the Special Issue Phytofactories: From Lab to Applications)

► Show Figures

Figure 1

25 pages, 2247 KB

Open AccessArticle

Transcriptomic Analysis of Adult Mouse Cardiac Stromal Cells Using Single-Cell qRT-PCR

by Rita Alonaizan, Patricia Chaves-Guerrero, Sara Samari, Michela Noseda, Nicola Smart and Carolyn Carr

Cells 2026, 15(4), 384; https://doi.org/10.3390/cells15040384 - 23 Feb 2026

Viewed by 480

Abstract

Fate-mapping studies have challenged the longstanding view of the adult mammalian heart as a post-mitotic organ, suggesting limited cardiomyocyte renewal. This has spurred efforts to determine whether selected cardiac stromal cells have regenerative potential; however, their contribution to cardiac regeneration has been found [...] Read more.

Fate-mapping studies have challenged the longstanding view of the adult mammalian heart as a post-mitotic organ, suggesting limited cardiomyocyte renewal. This has spurred efforts to determine whether selected cardiac stromal cells have regenerative potential; however, their contribution to cardiac regeneration has been found to be minimal compared with that of cardiomyocyte proliferation. Despite this, transplantation of some cardiac stromal cell populations has shown therapeutic potential through paracrine signalling. The identity of the paracrine-active stromal cell populations remains unclear due to overlapping characteristics with other cardiac stromal cell populations, such as fibroblasts, mesenchymal cells, and pericytes. This study sought to clarify the transcriptional identity and heterogeneity of adult mouse cardiac stromal cells by developing a cardiac collagenase–trypsin protocol and comparing it to the established method for isolating cardiosphere-derived cells (CDCs). This novel protocol resulted in a higher cell yield and shorter expansion time, and the resulting cells showed superior survival under serum starvation compared to commercially acquired cardiac fibroblasts (CFs). Single-cell qRT-PCR analysis revealed that collagenase–trypsin cells (CTs) and CDCs share similar gene expression profiles, distinct from those of CFs. Notably, CTs exhibited higher expression of Tcf21 and lower expression of Tbx5, suggesting an epicardial-derived fibroblast phenotype, whereas Tbx5 was enriched in CDCs and CFs, reflecting heterogeneity within the cardiac fibroblast compartment. This study offers insights into the complex identity of cardiac stromal cells and concludes that CTs closely resemble CDCs but can be generated more rapidly, making them a robust and efficient source of paracrine-active cardiac stromal cells. Full article

(This article belongs to the Special Issue Advances in Cardiomyocyte and Stem Cell Biology in Heart Disease)

► Show Figures

Figure 1

22 pages, 12173 KB

Open AccessArticle

A Comprehensive Adenoid Cystic Carcinoma-Derived Organoid Platform for Disease Modeling and Drug Screening Captures Interpatient Heterogeneity

by Yingyue Chai, Yi Sui, Xinyuan Zhang, Shang Xie, Yifan Kang, Yanrui Feng, Xiaofeng Shan and Zhigang Cai

Cells 2026, 15(4), 383; https://doi.org/10.3390/cells15040383 - 23 Feb 2026

Viewed by 670

Abstract

Salivary adenoid cystic carcinoma (ACC) is a highly aggressive salivary gland malignancy characterized by infiltrative growth patterns that hinder complete resection. Lacking effective chemotherapy, recurrent or metastatic ACC remains clinically incurable. This research aimed to develop an efficient culture system for ACC organoids, [...] Read more.

Salivary adenoid cystic carcinoma (ACC) is a highly aggressive salivary gland malignancy characterized by infiltrative growth patterns that hinder complete resection. Lacking effective chemotherapy, recurrent or metastatic ACC remains clinically incurable. This research aimed to develop an efficient culture system for ACC organoids, which can preserve tumor heterogeneity and establish a reliable drug screening platform. Under our optimized culture conditions, ACC organoids grew rapidly and successfully recapitulated three characteristic histopathological patterns. Whole-genome sequencing (WGS) further confirmed they mirrored the genomic features of their parental tumors, including significantly mutated genes, non-coding regulatory region mutations, copy number variation, and minor allele frequency. RNA sequencing confirmed that ACC organoids recapitulated the MYB-NFIB fusion gene. At the protein level, these organoids contained multiple cellular components, including epithelial cells, mesenchymal cells, K7+ duct cells, a-SMA+ myoepithelial cells, K5+ basement membrane cells, and CD44+ tumor stem cells, with proper spatial distribution patterns. With an 88% success rate, the first ACC organoid platform, incorporating normal salivary gland (SG) organoids as toxicity controls, enabled high-throughput drug testing within two weeks. In conclusion, we developed an efficient culture system for ACC organoids that can preserve tumor heterogeneity and establish a reliable drug screening platform for mechanistic studies and personalized precision therapy research. Full article

(This article belongs to the Section Stem Cells)

► Show Figures

Graphical abstract

25 pages, 924 KB

Open AccessReview

Brain Ketone Bodies in Health, Evolution and Disease

by Pierre Bougnères

Cells 2026, 15(4), 382; https://doi.org/10.3390/cells15040382 - 23 Feb 2026

Viewed by 1374

Abstract

Ketone bodies (KBs) are the only energy substrates oxidized by the brain, whose concentration in the circulation can greatly increase when a physiological situation requires it. For example, when an adult human fasts for two days, circulating KBs rise twenty-fold from ~0.1 to [...] Read more.

Ketone bodies (KBs) are the only energy substrates oxidized by the brain, whose concentration in the circulation can greatly increase when a physiological situation requires it. For example, when an adult human fasts for two days, circulating KBs rise twenty-fold from ~0.1 to ~2 mM. As a fuel, KBs provide the brain with acetyl-CoA that produces ATP or glutamate, notably in certain brain regions. Remarkably, KBs activate the expression of their own cerebral transporters and KB-utilizing enzymes so that circulating levels determine cerebral utilization of KBs. Throughout evolution, the energetic role of KBs has been crucial for the metabolic homeostasis of humans endowed with a large brain and facing unpredictable periods of food shortage. Paradoxically, the brain of modern, regularly fed humans whose ordinary blood KBs are ~0.1 mM, has access to much fewer circulating sources of energy than that of their distant ancestors. KBs can modify certain proteins post-translationally, for example, histones through lysine-butyrylation. KBs could act as short- or long-term epigenetic messengers. These properties of KBs might allow a fetus to directly sense maternal starvation and adapt their cerebral metabolism to this situation, possibly preparing for nutritional constraints in extra-uterine life. KB transcriptional and epigenetic properties could also enable the postnatal organism to retain a molecular memory of its own starvation episodes. No other energy substrate, such as glucose or lactate, has such capacities. Medicine turned its attention to KBs a century ago. Indeed, KBs are the only energy substrates whose circulating levels can be increased, and nutritional interventions can alter them under free-living conditions. This property opens broad prospects for ketogenic diets (KDs) to prevent or rescue neurodegenerative diseases characterized by glucose hypometabolism, notably Alzheimer’s disease (AD). However, KDs have not yet found real medical applications, for reasons that are discussed. Full article

► Show Figures

Graphical abstract

26 pages, 3645 KB

Open AccessArticle

WBP2 Attenuates Metformin Response in HER2-Positive Breast Cancer Cells by Repressing AMPK Activation and Inducing a Lower AMP:ATP Ratio State Through Enhanced ATP Production

by Hexian Lin, Shin-Ae Kang, Fei Xie, Yvonne Xinyi Lim, Sock Hong Seah, Amir Sabbaghian, Ssu-Yi Lu, Ting Gang Chew, Lih-Wen Deng, Shu Wang, E-Shyong Tai and Yoon Pin Lim

Cells 2026, 15(4), 381; https://doi.org/10.3390/cells15040381 - 23 Feb 2026

Viewed by 731

Abstract

Metformin is an antidiabetic drug that has been tested widely as an anti-cancer agent. However, data from clinical trials have been mixed. Evidence for metformin’s efficacy in HER2+ breast cancer exists. Hence, we evaluated whether WBP2, a HER2-coamplified gene, can regulate the response [...] Read more.

Metformin is an antidiabetic drug that has been tested widely as an anti-cancer agent. However, data from clinical trials have been mixed. Evidence for metformin’s efficacy in HER2+ breast cancer exists. Hence, we evaluated whether WBP2, a HER2-coamplified gene, can regulate the response of HER2+ breast cancer to metformin. Identification of biomarkers for predicting metformin response has implications in repurposing metformin for precision oncology. The effect of WBP2 on breast cancer response to metformin was studied using in vitro and mouse models. The mechanism of WBP2 on metformin-induced AMPK activation was elucidated, and its co-expression with p-AMPK was examined in clinical specimens using IHC. RNA-seq analyses were performed to elucidate WBP2’s mechanism in energy metabolism. WBP2 inhibited the metformin response of HER2+ breast cancer in vitro and in vivo. These effects were concomitant with WBP2-mediated repression of metformin-induced AMPK activation and mTOR inhibition in HER2+ breast cancer cells, a lower AMP:ATP ratio state, and enhanced glycolytic capacity and mitochondria respiration. Analysis of HER2-positive breast cancer samples supports the negative correlation between WBP2 expression and activated AMPK observed in vitro. RNA-seq analysis revealed the potential mechanism of WBP2 in regulating ATP production processes and preferential effect of WBP2 on metformin response in HER2+ breast cancer. This study reported a novel role of WBP2 in cancer metabolism and energetics that contributes new insights into the molecular etiology of cancer. WBP2 may be a biomarker for patient stratification, paving the way towards repurposing metformin for precision oncology. Full article

► Show Figures

Figure 1

15 pages, 487 KB

Open AccessReview

Determinants of Efficacy and Optimization of Chimeric Antigen Receptor T-Cell Therapy for Treating Multiple Myeloma: Current Status and Future Perspectives

by Hiroshi Yasui, Noriko Doki, Wei Yan, Kohzoh Imai and Tadao Ishida

Cells 2026, 15(4), 380; https://doi.org/10.3390/cells15040380 - 23 Feb 2026

Viewed by 650

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed and refractory multiple myeloma (MM), with BCMA-directed products demonstrating unprecedented response rates in heavily pretreated patients. Despite these advances, variabilities in response durability, treatment-related toxicities, and the emergence of resistance underscore [...] Read more.

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed and refractory multiple myeloma (MM), with BCMA-directed products demonstrating unprecedented response rates in heavily pretreated patients. Despite these advances, variabilities in response durability, treatment-related toxicities, and the emergence of resistance underscore the need for strategies that extend beyond CAR construct design alone. Accumulating evidence has indicated that the therapeutic outcomes of this approach are determined by a complex interplay between tumor burden, antigen dynamics, CAR T-cell functional fitness, and host immune context at the time of infusion. Effector-to-target balance and antigen load, in particular, have emerged as modifiable biological determinants of efficacy and safety, with pre-infusion disease control and response to bridging therapy exerting a profound influence on post-infusion CAR T-cell expansion, persistence, and clinical outcomes. Soluble BCMA (sBCMA) has also gained increasing attention as a practical biomarker that integrates tumor burden and antigen dynamics to facilitate the biologically informed optimization of treatment timing and patient selection. In addition to tumor- and antigen-related factors, the intrinsic properties of CAR T-cell products—including the spatial organization and clustering of CAR molecules on the T-cell surface—represent an additional layer of biological determinants that correlate with treatment responses. The quantitative functional assessment of CAR T-cell products may complement conventional clinical and tumor-based biomarkers and improve the prediction of therapeutic potency prior to infusion. This review summarizes recent advances in CAR T-cell therapy for treating MM, focusing on key mechanisms of resistance, the optimization of pre-infusion disease control, the integration of biological markers into clinical decision-making, and emerging combinations and sequential strategies. We also propose a design-oriented and patient-centered framework that integrates CAR engineering with disease biology and host immune factors to enhance the consistency, durability, and safety of CAR T-cell therapy. Such biologically guided optimization strategies will likely prove critical for fully realizing the transformative potential of CAR T-cell therapy across the evolving treatment continuum of MM. Full article

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

► Show Figures

Figure 1

30 pages, 5719 KB

Open AccessArticle

Development of a 3D Skin Model for Studying Melanoma Progression

by Dragana P. C. de Barros, Sara Ventura, Madalena Duque, Vanessa Ribeiro, Ana Sofia Lopes, Rita Zilhão, Ana Rita Carlos and Abel Oliva

Cells 2026, 15(4), 379; https://doi.org/10.3390/cells15040379 - 23 Feb 2026

Viewed by 490

Abstract

Despite advances in the treatment of cutaneous melanoma, there is still a high percentage of patients who fail to respond or develop resistance to treatment. Establishing robust in vitro melanoma models will enable mechanism-based drug screening while reducing animal testing. In this work, [...] Read more.

Despite advances in the treatment of cutaneous melanoma, there is still a high percentage of patients who fail to respond or develop resistance to treatment. Establishing robust in vitro melanoma models will enable mechanism-based drug screening while reducing animal testing. In this work, a three-dimensional (3D) melanoma skin model (3DMSM) was developed on a porous scaffold. The culture of three melanoma cell lines (SKMEL-1, A375, and G361) in co-culture with human fibroblasts, melanocytes, and keratinocytes allowed the formation of the dermis, and stratified epidermis. Tumors were established in this model using two methodologies: adding previously formed melanoma cell aggregates (CA) or seeding melanoma cells directly into the dermis (CD). In this model, melanoma cells remain in their original microenvironment and, after proliferation, invade the basal layer. The model recapitulates correct melanocyte localization, epidermal disruption, extracellular matrix (ECM) remodeling, including collagen deposition, and epithelial-to-mesenchymal transition (EMT). Additionally, the cytokine profiles studied indicate that the model could mirror the inflammatory and immune-evasive traits of melanoma. Overall, 3DMSM provides a useful tool for understanding the mechanisms of melanoma progression and invasion, and for developing personalized medicine strategies through the implementation of a patient-derived model. Full article

(This article belongs to the Special Issue Recent Advances in Extracellular-Intracellular Communication and Cancer Therapies)

► Show Figures

Figure 1

24 pages, 385 KB

Open AccessReview

Autoimmune Ocular Surface Disorders: From Molecular Immunopathogenesis to Regenerative and Surgical Therapeutics

by Wojciech Luboń, Marta Świerczyńska, Katarzyna Jadczyk-Sorek and Dorota Wyględowska-Promieńska

Cells 2026, 15(4), 378; https://doi.org/10.3390/cells15040378 - 22 Feb 2026

Viewed by 594

Abstract

Autoimmune ocular surface diseases represent a complex group of disorders in which systemic immune dysregulation triggers chronic inflammation, epithelial dysfunction, and progressive tissue fibrosis. Systemic lupus erythematosus, primary Sjögren’s syndrome, and ocular cicatricial pemphigoid are the principal entities linking systemic autoimmunity to ocular [...] Read more.

Autoimmune ocular surface diseases represent a complex group of disorders in which systemic immune dysregulation triggers chronic inflammation, epithelial dysfunction, and progressive tissue fibrosis. Systemic lupus erythematosus, primary Sjögren’s syndrome, and ocular cicatricial pemphigoid are the principal entities linking systemic autoimmunity to ocular surface pathology. These conditions share convergent mechanisms—including dysregulated cytokine signaling (IFN-I, IL-6, and IL-17), complement activation, and epithelial–mesenchymal transition—culminating in tear film instability and visual impairment. Recent advances in molecular immunology and omics profiling have elucidated disease-specific pathways and identified actionable therapeutic targets. Conventional immunosuppressants such as corticosteroids and cyclosporine remain fundamental, yet emerging biologics targeting BAFF, IFNAR, and JAK/STAT signaling—alongside regenerative strategies employing mesenchymal and induced pluripotent stem cells—are transforming disease management. Parallel innovations in amniotic membrane transplantation, keratoprosthesis, and bioengineered corneal scaffolds integrate structural reconstruction with immune modulation. Furthermore, the convergence of multi-omics analytics, artificial intelligence-assisted diagnostics, and microbiome-based immunomodulation heralds a new era of precision ophthalmology. This review synthesizes current molecular insights, clinical observations, and translational advances that collectively redefine autoimmune ocular surface diseases—from chronic inflammatory disorders into a targetable, regenerative, and potentially reversible spectrum of conditions. Full article

(This article belongs to the Special Issue Ocular Surface and Adnexal Diseases: Molecular Mechanisms and Treatment Progresses)

15 pages, 1742 KB

Open AccessArticle

CHI3L1 Expression in Chordoma: Implications for Immunotherapeutic Intervention

by Beatrice Campilan, Christian Godinez, Jonathan Arditi, Jessica Ding, Kaylee Gallagher, Andrew Fogarty, Christian Schroeder, Madison J. Michles, Weston de Lomba, Joselynn Wallace, John Santiago, Michael Punsoni, Suchitra Kamle, Jack A. Elias, Christine Lee, Ziya L. Gokaslan, Margot Martinez-Moreno and Patricia L. Zadnik Sullivan

Cells 2026, 15(4), 377; https://doi.org/10.3390/cells15040377 - 22 Feb 2026

Viewed by 477

Abstract

Chordomas are rare, highly morbid tumors arising from notochordal progenitor cells along the spinal axis, associated with severe neurological complications and high recurrence rates. Their resistance to conventional therapies and limited options beyond surgical resection and high-dose radiation underscore the urgent need for [...] Read more.

Chordomas are rare, highly morbid tumors arising from notochordal progenitor cells along the spinal axis, associated with severe neurological complications and high recurrence rates. Their resistance to conventional therapies and limited options beyond surgical resection and high-dose radiation underscore the urgent need for novel therapeutic targets. Publicly available preliminary RNA sequencing data from the Chordoma Foundation identified chitinase-3-like 1 (CHI3L1), a secreted glycoprotein implicated in immune checkpoint regulation and epithelial–mesenchymal transition (EMT), as a promising candidate for chordoma immunotherapy. Yet, the comprehensive function of CHI3L1 in chordoma immune response remains unclear. To evaluate its presence in chordoma, we employed RNA-based analyses alongside enzyme-linked immunosorbent assays (ELISA) on commercially available chordoma cell lines (JHC7, U-CH12, U-CH1, U-CH1-N) and human chordoma tumor specimens. Our results demonstrate elevated CHI3L1 expression in chordoma cells relative to notochordal precursors, with comparative analyses revealing higher CHI3L1 expression in the primary tumor relative to recurrent samples. These findings suggest the potential role of CHI3L1 in chordoma tumorigenesis, emphasizing its relevance as a biomarker and therapeutic target for primary tumors. Future studies are necessary to elucidate the mechanistic role of CHI3L1 in chordoma immune evasion and to explore targeted interventions that may improve patient outcomes in this aggressive cancer. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Novel Therapeutic Strategies in Chordoma)

► Show Figures

Graphical abstract

18 pages, 3627 KB

Open AccessArticle

LncRNA RORB-IT1 Encoding a Micropeptide Regulates Progesterone Synthesis, Proliferation and Apoptosis in Chicken Granulosa Cells

by Jie Cao, Qingqing Wei, Li Kang, Yi Sun and Yunliang Jiang

Cells 2026, 15(4), 375; https://doi.org/10.3390/cells15040375 - 22 Feb 2026

Viewed by 518

Abstract

Ovarian follicular development determines the egg-laying performance in chickens. Besides hormonal signaling, epigenetic and post-transcriptional regulators, long non-coding RNAs (lncRNAs) also play a vital role in follicular development. We previously identified that RAR-related orphan receptor B-intronic transcript 1 (RORB-IT1), a novel [...] Read more.

Ovarian follicular development determines the egg-laying performance in chickens. Besides hormonal signaling, epigenetic and post-transcriptional regulators, long non-coding RNAs (lncRNAs) also play a vital role in follicular development. We previously identified that RAR-related orphan receptor B-intronic transcript 1 (RORB-IT1), a novel lncRNA located in the intron of RORB, was differentially expressed in chicken pre-hierarchical and hierarchical follicular granulosa cells (Post-GCs). However, it remains unknown whether RORB-IT1 participates in regulating the development of chicken ovarian follicles. In this study, we further characterized the expression pattern of RORB-IT1 and explored its role in regulating the progesterone synthesis, proliferation and apoptosis of chicken Post-GCs. The results showed that RORB-IT1, with a full length of 383 bp, exhibits a uniform distribution in both the cytoplasm and nucleus of chicken Post-GCs. RORB-IT1 was specifically expressed in Post-GCs and upregulated by follicle-stimulating hormone (FSH), progesterone (P4) and estradiol (E2) in a dose-dependent manner. Functionally, RORB-IT1 promoted P4 synthesis and proliferation, while inhibiting the apoptosis of Post-GCs. Furthermore, we demonstrated that RORB-IT1 encoded a functional micropeptide exhibiting dual localization in both cytoplasmic and nuclear compartments. This micropeptide enhanced progesterone synthesis and proliferation, but paradoxically induced the apoptosis of Post-GCs when overexpressed independently. Collectively, this study uncovered the expression pattern and function of RORB-IT1 in chicken Post-GCs and provided a theoretical basis for improving the egg-laying performance in chickens. Full article

► Show Figures

Graphical abstract

25 pages, 1819 KB

Open AccessReview

Gene Therapy Advancements in Age-Related Macular Degeneration Treatment

by Efstratia Amaxilati, Eleftherios Chatzimichail, Georgios N. Tsiropoulos, Lorenzo Motta, Theo Empeslidis, Zisis Gatzioufas and Georgios D. Panos

Cells 2026, 15(4), 376; https://doi.org/10.3390/cells15040376 - 21 Feb 2026

Viewed by 826

Abstract

Age-related macular degeneration (AΜD) remains a leading cause of irreversible vision loss. Ιn neovascular AΜD (nAΜD), frequent intravitreal anti-VΕGF injections create substantial treatment burden, while approved therapies for geographic atrophy (GA) provide modest slowing of progression. Ocular gene therapy aims to achieve sustained [...] Read more.

Age-related macular degeneration (AΜD) remains a leading cause of irreversible vision loss. Ιn neovascular AΜD (nAΜD), frequent intravitreal anti-VΕGF injections create substantial treatment burden, while approved therapies for geographic atrophy (GA) provide modest slowing of progression. Ocular gene therapy aims to achieve sustained intraocular expression of therapeutic proteins after a single administration. Τhis review summarises the biological rationale, vector platforms, and delivery routes relevant to AΜD, with emphasis on adeno-associated virus (AAV) systems, capsid engineering, and compartment-specific administration (intravitreal, subretinal, and suprachoroidal). We synthesise the clinical landscape for sustained anti-VΕGF expression approaches in nAΜD and complement-modulating strategies for GA, and highlight how trials increasingly prioritise injection-burden reduction, anatomical endpoints, and biomarkers of target engagement. Κey challenges include intraocular inflammation and neutralising antibodies (particularly with intravitreal dosing), variability and durability of transgene expression, surgical risks associated with subretinal delivery, and practical constraints related to manufacturing scale, cost, and long-term safety surveillance for non-removable therapies. Overall, gene therapy offers a plausible route towards durable, mechanism-targeted AΜD management, but its clinical role will depend on robust controlled trials and multi-year follow-up. Full article

(This article belongs to the Special Issue Cell Biology of the Eye: Development, Disorders, and Repair)

► Show Figures

Figure 1

19 pages, 715 KB

Open AccessSystematic Review

MicroRNA Expression Profile in Endometriosis and Endometriosis-Associated Ovarian Cancer—Systematic Review

by Maria Szubert, Iwona Gabriel, Aleksander Rycerz, Monika Golińska and Jacek R. Wilczyński

Cells 2026, 15(4), 374; https://doi.org/10.3390/cells15040374 - 20 Feb 2026

Viewed by 695

Abstract

Endometriosis-associated ovarian cancer comprises a special group of ovarian cancers that most probably originate from endometriosis foci. Several in vitro studies have shown that microRNA (miRNA) plays an important role in this carcinogenesis. Our goal was to establish if a distinct miRNA profile [...] Read more.

Endometriosis-associated ovarian cancer comprises a special group of ovarian cancers that most probably originate from endometriosis foci. Several in vitro studies have shown that microRNA (miRNA) plays an important role in this carcinogenesis. Our goal was to establish if a distinct miRNA profile can be associated with endometriosis and endometriosis-associated ovarian cancer with their potential causal relationship, and whether such a profile could be used clinically to prognose carcinogenesis in endometriosis foci. We conducted a systematic search according to PRISMA guidelines, registered at PROSPERO (number CRD42021245606). The search encompassed whole Pubmed, Cochrane and Medline databases to 1 May 2025 and the search strategy included the following [MeSH] terms: ‘miRNAs’ or ‘microRNAs’ or ‘miR’ and ‘ovarian cancer’ and ‘endometriosis’. Our ultimate inclusion criterion was that studies must simultaneously evaluate miRNA expression in endometriosis, regardless of its form and stage, and in endometriosis-associated ovarian cancer (EAOC), as only data generated under identical experimental conditions and using the same controls are truly comparable. The quality of the data was assessed using The Newcastle-Ottawa scale (NOS) and ROBINS-I tool. Our final analysis included 13 studies, comprising 608 patients and over 1000 miRNA molecules. Among those only five manuscripts presented raw data for each miRNA studied. Although several authors declared high sensitivity and specificity for one or more miRNA in distinguishing between endometriosis and endometriosis-associated ovarian cancer, a meta-analysis could not be performed due to the high heterogeneity of the studied samples. We concluded that there is not enough publicly available raw data to establish a set of miRNAs capable of differentiating between the two diseases and of prognosing carcinogenesis. The greatest limitation lies in the use of various standardized reference gene sets, which makes it impossible to compare relative miRNA expression across studies. New data from the next generation sequencing (NGS) experiments would overcome issues related to reference and control genes. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Ovarian Cancer and Therapeutic Strategies)

► Show Figures

Figure 1

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

Viewed by 635

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

Graphical abstract

29 pages, 1387 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

Viewed by 799

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

► Show Figures

Figure 1

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

Viewed by 721

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

Graphical abstract

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

Viewed by 482

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

Viewed by 1120

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

Viewed by 610

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

Graphical abstract

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

Viewed by 711

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

Graphical abstract

33 pages, 1608 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

Viewed by 929

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)

► Show Figures

Figure 1

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

Viewed by 779

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

Viewed by 874

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

Viewed by 696

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

45 pages, 3426 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

Viewed by 964

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)

► Show Figures

Graphical abstract

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

Viewed by 527

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

Viewed by 507

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

20 pages, 7186 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

Viewed by 670

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

Viewed by 656

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

19 pages, 8268 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

Viewed by 424

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)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Cells, Volume 15, Issue 4 (February-2 2026) – 75 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI