Cells

15 pages, 1077 KB

Open AccessArticle

Long Non-Coding RNA MALAT1 Regulates HMOX1 in Sickle Cell Disease-Associated Pulmonary Hypertension

by Viranuj Sueblinvong, Sarah S. Chang, Jing Ma, David R. Archer, Solomon Ofori-Acquah, Roy L. Sutliff, Changwon Park, C. Michael Hart, Benjamin T. Kopp and Bum-Yong Kang

Cells 2026, 15(2), 154; https://doi.org/10.3390/cells15020154 (registering DOI) - 15 Jan 2026

Abstract

Pulmonary hypertension (PH) causes morbidity and mortality in sickle cell disease (SCD). The release of heme during hemolysis triggers endothelial dysfunction and contributes to PH. Long non-coding RNAs (lncRNAs) may play a pivotal role in endothelial dysfunction and PH pathogenesis. This study assessed [...] Read more.

Pulmonary hypertension (PH) causes morbidity and mortality in sickle cell disease (SCD). The release of heme during hemolysis triggers endothelial dysfunction and contributes to PH. Long non-coding RNAs (lncRNAs) may play a pivotal role in endothelial dysfunction and PH pathogenesis. This study assessed the regulatory role of the lncRNA–heme oxygenase-1 (HMOX1) axis in SCD-associated PH pathogenesis. Total RNAs were isolated from the lungs of 15–17-week-old sickle cell (SS) mice and littermate controls (AA) mice and subjected to lncRNA expression profiling using the Arrystar™ lncRNA array. Volcano plot filtering was used to screen for differentially expressed lncRNAs and mRNAs with statistical significance (fold change > 1.8, p < 0.05). A total of 3915 lncRNAs were upregulated and a total of 3545 lncRNAs were downregulated in the lungs of SS mice compared to AA mice. To validate differentially expressed lncRNAs, six upregulated lncRNAs and six downregulated lncRNAs were selected for quantitative PCR. MALAT1 expression was significantly upregulated in the lungs of SS mice and in hemin-treated human pulmonary artery endothelial cells (HPAECs), suggesting that hemolysis induces MALAT1. Functional studies revealed that MALAT1 depletion increased, while MALAT1 overexpression decreased, the endothelial dysfunction markers endothelin-1 (ET-1) and vascular cell adhesion molecule-1 (VCAM1), indicating a protective role of MALAT1 in maintaining endothelial homeostasis. In vivo, adenoviral MALAT1 overexpression attenuated PH, right ventricular hypertrophy (RVH), vascular remodeling, and reduced ET-1 and VCAM1 expression in SS mice. Given that HMOX1 protects endothelial cells during hemolysis, we observed that HMOX1 expression and activity were elevated in SS mouse lungs and hemin-treated HPAECs. HMOX1 knockdown enhanced ET-1 and VCAM1 expression, confirming its endothelial-protective function. Importantly, MALAT1 overexpression increased HMOX1 expression and activity, whereas MALAT1 knockdown reduced HMOX1 levels and mRNA stability. Collectively, these findings identify MALAT1 as a protective regulator that mitigates endothelial dysfunction, vascular remodeling, and PH in SCD, at least in part through the induction of HMOX1. These results suggest that SCD modulates the MALAT1–HMOX1 axis, and further characterization of MALAT1 function may provide new insights into SCD-associated endothelial dysfunction and PH pathogenesis, as well as identify novel therapeutic targets. Full article

(This article belongs to the Special Issue Sickle Cell Disease: Pathogenesis, Diagnosis and Treatment)

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37 pages, 2633 KB

Open AccessReview

Organ-Specific Regulation of Systemic Aging: Focus on the Brain, Skeletal Muscle, and Gut

by Jie Fu, Chengrui Liu, Yulin Shu, Yuxin Jiang, Ping Li and Kai Yao

Cells 2026, 15(2), 153; https://doi.org/10.3390/cells15020153 - 14 Jan 2026

Abstract

As global population aging accelerates, the growing burden of age-related diseases is driving a shift in medical research from single-disease treatment to interventions targeting the aging process itself. Organ-specific interventions have emerged as a promising strategy to modulate systemic aging. Among organs, the [...] Read more.

As global population aging accelerates, the growing burden of age-related diseases is driving a shift in medical research from single-disease treatment to interventions targeting the aging process itself. Organ-specific interventions have emerged as a promising strategy to modulate systemic aging. Among organs, the brain, muscle, and gut have attracted particular attention due to their central roles in neural regulation, metabolic homeostasis, and immune balance. In this review, we focus on these three key organs, systematically summarizing their roles and regulatory mechanisms in organismal aging and discussing how exercise influences the aging process by affecting these organs. Crucially, we propose a novel “local-to-global” regulatory model, positing that preserving homeostasis in these specific tissues is sufficient to orchestrate systemic anti-aging effects. This work represents a conceptual advance by providing the theoretical rationale to move beyond non-specific systemic treatments toward precise, organ-targeted interventions. Full article

17 pages, 7354 KB

Open AccessArticle

Adrenomedullin-RAMP2 Enhances Lung Endothelial Cell Homeostasis Under Shear Stress

by Yongdae Yoon, Sean R. Duffy, Shannon E. Kirk, Kamoltip Promnares, Pratap Karki, Anna A. Birukova, Konstantin G. Birukov and Yifan Yuan

Cells 2026, 15(2), 152; https://doi.org/10.3390/cells15020152 (registering DOI) - 14 Jan 2026

Abstract

Analysis of pulmonary vascular dysfunction in various lung pathologies remains challenging due to the lack of functional ex vivo models. Paracrine signaling in the lung plays a critical role in regulating endothelial maturation and vascular homeostasis. Previously, we employed single-cell RNA-sequencing (scRNAseq) to [...] Read more.

Analysis of pulmonary vascular dysfunction in various lung pathologies remains challenging due to the lack of functional ex vivo models. Paracrine signaling in the lung plays a critical role in regulating endothelial maturation and vascular homeostasis. Previously, we employed single-cell RNA-sequencing (scRNAseq) to systematically map ligand–receptor (L/R) interactions within the lung vascular niche. However, the functional impact of these ligands on endothelial biology remained unknown. Here, we systematically evaluated selected ligands in vitro to assess their effects on endothelial barrier integrity, anti-inflammatory responses, and phenotypic maturation. Among the top soluble ligands, we found that adrenomedulin (ADM) exhibited superior barrier enhancing effect on human pulmonary endothelial cell monolayers, as evidenced by electrical cell impedance sensing (ECIS) and XperT assays. ADM also exhibited anti-inflammatory properties, decreasing ICAM1 and increasing IkBa expression in a dose-dependent manner. Perfusion is commonly used in bioengineered vascular model systems. Shear stress (15 dynes/cm²) alone increased endothelial characteristics, including homeostatic markers such as CDH5, NOS3, TEK, and S1PR1. ADM treatment maintained the enhanced level of these markers under shear stress and further improved anti-coagulation by increasing THBD and decreasing F3 expression and synergistically enhanced the expression of the native lung aerocyte capillary endothelial marker EDNRB. This effect was completely attenuated by a blockade of ADM receptor, RAMP2. Together, these findings identify ADM/RAMP2 signaling as a key paracrine pathway that enhances vascular barrier integrity, anti-inflammatory phenotype, and endothelial homeostasis, providing a framework for improving the physiological relevance of engineered vascular models. Full article

(This article belongs to the Collection The Endothelial Cell in Lung Inflammation)

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26 pages, 6754 KB

Open AccessArticle

Akhirin Functions as an Innate Immune Barrier to Preserve Neurogenic Niche Homeostasis During Mouse Brain Development

by Mikiko Kudo, Tenta Ohkubo, Taichi Sugawara, Takashi Irie, Jun Hatakeyama, Shigehiko Tamura, Kenji Shimamura, Tomohiko Wakayama, Naoki Matsuo, Kinichi Nakashima, Takahiro Masuda and Kunimasa Ohta

Cells 2026, 15(2), 151; https://doi.org/10.3390/cells15020151 - 14 Jan 2026

Abstract

Neurogenesis is tightly regulated by complex interactions among neural stem and progenitor cells (NSCs/NPCs), blood vessels, microglia, and extracellular matrix components within the neurogenic niche. In the embryonic brain, NSCs reside along the ventricular surface, where cerebrospinal fluid (CSF) directly regulates their proliferation. [...] Read more.

Neurogenesis is tightly regulated by complex interactions among neural stem and progenitor cells (NSCs/NPCs), blood vessels, microglia, and extracellular matrix components within the neurogenic niche. In the embryonic brain, NSCs reside along the ventricular surface, where cerebrospinal fluid (CSF) directly regulates their proliferation. Here, we identify Akhirin (AKH) as a critical regulator that preserves the integrity of the NSC niche during mouse brain development. At embryonic day 14.5, AKH is secreted and enriched at the apical surface of choroid plexus epithelial cells and the ventricular lining. Loss of AKH leads to increases the inflammatory cytokine expression in the CSF and disrupts NSC niche homeostasis. Furthermore, AKH is cleaved upon inflammatory stimulation, and its LCCL domain directly binds bacteria, thereby preventing their spread. These findings reveal that AKH functions as a protective barrier molecule within the developing neurogenic niche, providing immune protection and preserving NSC niche homeostasis during periods when the innate immune defenses are still immature. Full article

(This article belongs to the Section Stem Cells)

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19 pages, 352 KB

Open AccessReview

Ketones in Cardiovascular Health and Disease: An Updated Review

by Sanjiv Shrestha, Isis Harrison, Aminat Dosunmu and Ping Song

Cells 2026, 15(2), 150; https://doi.org/10.3390/cells15020150 - 14 Jan 2026

Abstract

Ketones are metabolites primarily produced by the liver and are utilized by various organs outside of the liver. Recent advances have demonstrated that ketones serve not only as alternative energy sources but also as signaling molecules. Research indicates that ketones can influence cancer [...] Read more.

Ketones are metabolites primarily produced by the liver and are utilized by various organs outside of the liver. Recent advances have demonstrated that ketones serve not only as alternative energy sources but also as signaling molecules. Research indicates that ketones can influence cancer development and metastasis, cardiac metabolic and structural remodeling, physical performance, vascular function, inflammation, and the aging process. Emerging evidence from preclinical and early-phase clinical studies suggests that strategies such as ketone salts, ketone esters, and the ketogenic diet may offer therapeutic benefits for conditions like heart failure, acute cardiac injury, diabetic cardiomyopathy, vascular complications, atherosclerosis, hypertension, and aortic aneurysm. This literature review updates the current understanding of ketone metabolism and its contributions to cardiovascular health and diseases. We highlight the underlying molecular mechanism with post-translational modification known as β-hydroxybutyrylation, which affects the fate and function of target proteins. Additionally, we discuss the therapeutic challenges associated with ketone therapy, the potential of using ketone levels as biomarkers for cardiovascular diseases, as well as gender- and age-specific differences in ketone treatment. Finally, we explore future research directions and what is needed to translate these new insights into cardiovascular medicine. Full article

(This article belongs to the Special Issue New Insights into Therapeutic Targets for Cardiovascular Diseases)

20 pages, 740 KB

Open AccessReview

Mitochondrial Metabolic Checkpoints in Human Fertility: Reactive Oxygen Species as Gatekeepers of Gamete Competence

by Sofoklis Stavros, Nikolaos Thomakos, Efthalia Moustakli, Nikoleta Daponte, Dimos Sioutis, Nikolaos Kathopoulis, Athanasios Zikopoulos, Ismini Anagnostaki, Chrysi Christodoulaki, Themos Grigoriadis, Ekaterini Domali and Anastasios Potiris

Cells 2026, 15(2), 149; https://doi.org/10.3390/cells15020149 - 14 Jan 2026

Abstract

Crucial regulators of gamete metabolism and signaling, mitochondria synchronize energy generation with redox equilibrium and developmental proficiency. Once thought of as hazardous byproducts, reactive oxygen species (ROS) are now understood to be vital signaling molecules that provide a “redox window of competence” that [...] Read more.

Crucial regulators of gamete metabolism and signaling, mitochondria synchronize energy generation with redox equilibrium and developmental proficiency. Once thought of as hazardous byproducts, reactive oxygen species (ROS) are now understood to be vital signaling molecules that provide a “redox window of competence” that is required for oocyte maturation, sperm capacitation, and early embryo development. This review presents the idea of mitochondrial metabolic checkpoints, which are phases that govern gamete quality and fertilization potential by interacting with cellular signaling, redox balance, and mitochondrial activity. Recent research shows that oocytes may sustain a nearly ROS-free metabolic state by blocking specific respiratory-chain components, highlighting the importance of mitochondrial remodeling in gamete competence. Evidence from in vitro and in vivo studies shows that ROS act as dynamic gatekeepers at critical points in oogenesis, spermatogenesis, fertilization, and early embryogenesis. However, assisted reproductive technologies (ARTs) may inadvertently disrupt this redox–metabolic equilibrium. Potential translational benefits can be obtained via targeted techniques that optimize mitochondrial function, such as modifying oxygen tension, employing mitochondria-directed antioxidants like MitoQ and SS-31, and supplementing with nutraceuticals like melatonin, CoQ10, and resveratrol. Understanding ROS-mediated checkpoints forms the basis for developing biomarkers of gamete competence and precision therapies to improve ART outcomes. By highlighting mitochondria as both metabolic sensors and redox regulators, this review links fundamental mitochondrial biology to clinical reproductive medicine. Full article

(This article belongs to the Collection Feature Papers in Mitochondria)

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19 pages, 963 KB

Open AccessReview

Impact of Menopause and Associated Hormonal Changes on Spine Health in Older Females: A Review

by Julia Chagas, Gabrielle Gilmer, Gwendolyn Sowa and Nam Vo

Cells 2026, 15(2), 148; https://doi.org/10.3390/cells15020148 - 14 Jan 2026

Abstract

Low back pain (LBP) represents a major societal and economic burden, with annual costs in the United States estimated at $90–134.5 billion. LBP disproportionately impacts postmenopausal women relative to age-matched men, suggesting a role for sex-specific biological factors. Although the mechanisms underlying this [...] Read more.

Low back pain (LBP) represents a major societal and economic burden, with annual costs in the United States estimated at $90–134.5 billion. LBP disproportionately impacts postmenopausal women relative to age-matched men, suggesting a role for sex-specific biological factors. Although the mechanisms underlying this disparity are not fully understood, hormonal imbalance during menopause may contribute to LBP pathophysiology. This narrative review aimed to elucidate the impact of menopause on LBP, with emphasis on hormonal effects on spinal tissues and systemic processes. A literature search was conducted, followed by screening of titles, abstracts, and full texts of original clinical studies, preclinical research using human or animal samples, and relevant reviews. Rigour and reproducibility were evaluated using the ARRIVE Guidelines and the Modified Downs & Black Checklist. Evidence indicates that menopause is associated with changes in intervertebral discs, facet joint, ligamentum flavum, skeletal muscle, sympathetic innervation, and systemic systems such as the gut microbiome. However, most findings are correlational rather than causal. Evidence supporting hormone replacement therapy for LBP remains inconclusive, whereas exercise and other treatments, including parathyroid hormones, show more consistent benefits. Future studies should focus on causal mechanisms and adhere to rigour guidelines to improve translational potential. Full article

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

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22 pages, 9987 KB

Open AccessArticle

Network Hypoactivity in ALG13-CDG: Disrupted Developmental Pathways and E/I Imbalance as Early Drivers of Neurological Features in CDG

by Rameen Shah, Rohit Budhhraja, Silvia Radenkovic, Graeme Preston, Alexia Tyler King, Sahar Sabry, Charlotte Bleukx, Ibrahim Shammas, Lyndsay Young, Jisha Chandran, Seul Kee Byeon, Ronald Hrstka, Doughlas Y. Smith IV, Nathan P. Staff, Richard Drake, Steven A. Sloan, Akhilesh Pandey, Eva Morava and Tamas Kozicz

Cells 2026, 15(2), 147; https://doi.org/10.3390/cells15020147 - 14 Jan 2026

Abstract

Background: ALG13-CDG is an X-linked N-linked glycosylation disorder caused by pathogenic variants in the glycosyltransferase ALG13, leading to severe neurological manifestations. Despite the clear CNS involvement, the impact of ALG13 dysfunction on human brain glycosylation and neurodevelopment remains unknown. We hypothesize that ALG13-CDG [...] Read more.

Background: ALG13-CDG is an X-linked N-linked glycosylation disorder caused by pathogenic variants in the glycosyltransferase ALG13, leading to severe neurological manifestations. Despite the clear CNS involvement, the impact of ALG13 dysfunction on human brain glycosylation and neurodevelopment remains unknown. We hypothesize that ALG13-CDG causes brain-specific hypoglycosylation that disrupts neurodevelopmental pathways and contributes directly to cortical network dysfunction. Methods: We generated iPSC-derived human cortical organoids (hCOs) from individuals with ALG13-CDG to define the impact of hypoglycosylation on cortical development and function. Electrophysiological activity was assessed using MEA recordings and integrated with multiomic profiling, including scRNA-seq, proteomics, glycoproteomics, N-glycan imaging, lipidomics, and metabolomics. X-inactivation status was evaluated in both iPSCs and hCOs. Results: ALG13-CDG hCOs showed reduced glycosylation of proteins involved in ECM organization, neuronal migration, lipid metabolism, calcium homeostasis, and neuronal excitability. These pathway disruptions were supported by proteomic and scRNA-seq data and included altered intercellular communication. Trajectory analyses revealed mistimed neuronal maturation with early inhibitory and delayed excitatory development, indicating an E/I imbalance. MEA recordings demonstrated early network hypoactivity with reduced firing rates, immature burst structure, and shortened axonal projections, while transcriptomic and proteomic signatures suggested emerging hyperexcitability. Altered lipid and GlcNAc metabolism, along with skewed X-inactivation, were also observed. Conclusions: Our study reveals that ALG13-CDG is a disorder of brain-specific hypoglycosylation that disrupts key neurodevelopmental pathways and destabilizes cortical network function. Through integrated multiomic and functional analyses, we identify early network hypoactivity, mistimed neuronal maturation, and evolving E/I imbalance that progresses to compensatory hyperexcitability, providing a mechanistic basis for seizure vulnerability. These findings redefine ALG13-CDG as disorders of cortical network instability, offering a new framework for targeted therapeutic intervention. Full article

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18 pages, 1992 KB

Open AccessReview

Peptide Arrays as Tools for Unraveling Tumor Microenvironments and Drug Discovery in Oncology

by Anna Grab, Christoph Reißfelder and Alexander Nesterov-Mueller

Cells 2026, 15(2), 146; https://doi.org/10.3390/cells15020146 - 14 Jan 2026

Abstract

Peptide arrays represent a powerful tool for investigating a wide application field for biomedical questions. This review summarizes recent applications of peptide chips in oncology, with a focus on tumor microenvironment, metastasis, and drug mechanism of action for various cancer types. These high-throughput [...] Read more.

Peptide arrays represent a powerful tool for investigating a wide application field for biomedical questions. This review summarizes recent applications of peptide chips in oncology, with a focus on tumor microenvironment, metastasis, and drug mechanism of action for various cancer types. These high-throughput platforms enable the simultaneous screening of thousands of peptides. We report on recent achievements in peptide array technology for tumor microenvironments, an enhanced ability to decipher complex cancer-related signaling pathways, and characterization of cell-adhesion-mediating peptides. Furthermore, we highlight the applications in high-throughput drug screenings for development of immune therapies, e.g., the development of novel neoantigen therapies of glioblastoma. Moreover, epigenetic profiling using peptide arrays has uncovered new therapeutic targets across various cancer types with clinical impact. In conclusion, we discuss artificial intelligence-driven peptide array analysis as a tool to determine tumor origin and metastatic state, potentially transforming diagnostic approaches. These innovations promise to accelerate the development of precision cancer approaches. Full article

(This article belongs to the Special Issue Cancer Cell Signaling, Autophagy and Tumorigenesis)

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33 pages, 4569 KB

Open AccessArticle

Heterotypic 3D Model of Breast Cancer Based on Tumor, Stromal and Endothelial Cells: Cytokines Interaction in the Tumor Microenvironment

by Anastasia Leonteva, Alina Kazakova, Ekaterina Berezutskaya, Anna Ilyina, David Sergeevichev, Sergey Vladimirov, Maria Bogachek, Igor Vakhrushev, Pavel Makarevich, Vladimir Richter and Anna Nushtaeva

Cells 2026, 15(2), 145; https://doi.org/10.3390/cells15020145 - 14 Jan 2026

Abstract

The recreation of the tumor microenvironment remains a significant challenge in the development of experimental cancer models. The present study constitutes an investigation into the interconnection between tumor, endothelial and stromal cells in heterotypic breast cancer spheroids. The generation of models was achieved [...] Read more.

The recreation of the tumor microenvironment remains a significant challenge in the development of experimental cancer models. The present study constitutes an investigation into the interconnection between tumor, endothelial and stromal cells in heterotypic breast cancer spheroids. The generation of models was achieved through the utilization of MCF7, MDA-MB-231, and SK-BR-3 tumor cell lines, in conjunction with endothelial TIME-RFP cells and either cancer-associated (BrC4f) or normal (BN120f) fibroblasts, within ultra-low attachment plates. It was established that stromal cells, most notably fibroblasts, were conducive to the aggregation of tumor cells into spheroids and the formation of pseudovessels in close proximity to fibroblast bands. In contrast to the more aggressive tumor models MDA-MB-231 and SK-BR-3, microenvironment cells do not influence the migration ability of MCF7 tumor cells. Heterotypic spheroids incorporating CAFs demonstrated a more aggressive and immunosuppressive phenotype. Multiplex immunoassay analysis of cytokines, followed by STRING cluster analysis, was used to identify key processes including angiogenesis, invasion, stem cell maintenance, and immunosuppression. Furthermore, a cluster of cytokines (LIF, SDF-1, HGF, SCGFb) was identified as potentially involved in the regulation of PD-L1 expression by tumor cells. This finding reveals a potential mechanism of immune evasion and suggests new avenues for therapeutic investigation. Full article

(This article belongs to the Special Issue Cell-to-Cell Crosstalk as a Target of Therapies)

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23 pages, 1633 KB

Open AccessReview

TRPC3 and TRPC6: Multimodal Cation-Conducting Channels Regulating Cardiovascular Contractility and Remodeling

by Takuro Numaga-Tomita and Motohiro Nishida

Cells 2026, 15(2), 144; https://doi.org/10.3390/cells15020144 - 14 Jan 2026

Abstract

Transient receptor potential canonical (TRPC) channels function as multimodal cation channels that integrate chemical and mechanical cues to regulate cellular signaling. Among them, TRPC3 and TRPC6 have been studied primarily in the context of cardiovascular and renal physiology, and their roles in other [...] Read more.

Transient receptor potential canonical (TRPC) channels function as multimodal cation channels that integrate chemical and mechanical cues to regulate cellular signaling. Among them, TRPC3 and TRPC6 have been studied primarily in the context of cardiovascular and renal physiology, and their roles in other organ systems are now increasingly recognized. Although these channels are known to be activated downstream of phospholipase C (PLC) signaling, especially 1,2-diacylglycerol (DAG) production, their precise modes of activation under native physiological conditions remain incompletely understood. Recent structural and functional studies have greatly advanced our understanding of their primary activation by DAG. This review summarizes how decades of physiological analyses have revealed multiple modes of TRPC3 and TRPC6 channel activation beyond DAG gating, providing a broader perspective on their diverse regulatory mechanisms. This review also highlights recent progress in elucidating the channel properties, activation mechanisms, and the physiological as well as pathophysiological roles of TRPC3 and TRPC6 in cardiovascular contractility and remodeling, and discusses the remaining challenges that will lead to the establishment of TRPC3 and TRPC6 as validated therapeutic targets. Full article

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

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22 pages, 2780 KB

Open AccessReview

Hippo Signaling in the Lung: A Tale of Two Effectors—Yap Drives Airway Fate and Taz Drives Alveolar Differentiation

by Rachel Warren and Stijn P. J. De Langhe

Cells 2026, 15(2), 143; https://doi.org/10.3390/cells15020143 - 13 Jan 2026

Abstract

The mammalian lung operates under a biological paradox, requiring architectural fragility for gas exchange while maintaining robust regenerative plasticity to withstand injury. The Hippo signaling pathway has emerged as a central “rheostat” in orchestrating these opposing needs, yet the distinct roles of its [...] Read more.

The mammalian lung operates under a biological paradox, requiring architectural fragility for gas exchange while maintaining robust regenerative plasticity to withstand injury. The Hippo signaling pathway has emerged as a central “rheostat” in orchestrating these opposing needs, yet the distinct roles of its downstream effectors remain underappreciated. This review synthesizes recent genetic and mechanobiological advances to propose a “Tale of Two Effectors” model, arguing for the functional non-redundancy of YAP and TAZ. We posit that YAP functions to drive airway progenitor expansion, mechanical force generation, and maladaptive remodeling. Conversely, TAZ—regulated uniquely via transcriptional mechanisms and mechanotransduction—acts as an obligate driver of alveolar differentiation and adaptive repair through an NKX2-1 feed-forward loop. Furthermore, we introduce the “See-Saw” model of tissue fitness, where mesenchymal niche collapse releases the mechanical brake on the epithelium, triggering the bronchiolization characteristic of pulmonary fibrosis. Finally, we extend this framework to malignancy, illustrating how Small Cell Lung Cancer (SCLC) subtypes mirror these developmental and regenerative states. This integrated framework offers new therapeutic distinct targets for modulating tissue fitness and resolving fibrosis. Full article

(This article belongs to the Special Issue Mechanisms of Lung Growth and Regeneration)

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30 pages, 1723 KB

Open AccessArticle

Candidate Interaction Partners of Calpain-5 Suggest Clues to Its Involvement in Neovascular Inflammatory Vitreoretinopathy

by Jozsef Gal, Vimala Bondada, Rachel Crasta, Dorothy E. Croall, Calvin P. Vary and James W. Geddes

Cells 2026, 15(2), 142; https://doi.org/10.3390/cells15020142 - 13 Jan 2026

Abstract

Although calpain-5/CAPN5 is widely expressed in mammals, little is known regarding its functions. Pathogenic mutations of CAPN5 are causal for a devastating autoimmune eye disease, neovascular inflammatory vitreoretinopathy (NIV). To provide insight into both the physiological and pathological roles of CAPN5, it is [...] Read more.

Although calpain-5/CAPN5 is widely expressed in mammals, little is known regarding its functions. Pathogenic mutations of CAPN5 are causal for a devastating autoimmune eye disease, neovascular inflammatory vitreoretinopathy (NIV). To provide insight into both the physiological and pathological roles of CAPN5, it is essential to identify candidate interaction partners and possible substrates. Human SH-SY5Y neuroblastoma cells, transfected with full-length catalytically dead (Cys81Ala) CAPN5-3×FLAG, were used for anti-FLAG co-immunoprecipitation (co-IP) and quantitative proteomics using Sequential Window Acquisition of all THeoretical mass spectra (SWATH-MS). Fifty-one proteins were enriched at least four-fold, p < 0.01, relative to cells transfected with an empty FLAG vector. A high proportion (24/51) of candidate CAPN5 interaction partners are associated with protein quality control, including components of the chaperonin, chaperone, and ubiquitin–proteasome systems. Additional candidate interactors include tubulins, kinases, phosphatases, G proteins, and mitochondrial proteins. CAPN5 interactions for 14 of the candidate proteins were confirmed by co-IP and immunoblotting. Of these 14 proteins, 11 exhibited in vitro calcium-induced proteolysis following co-IP with WT CAPN5-3×FLAG. Impaired calcium-induced proteolysis of co-IP proteins was observed for the pathogenic CAPN5 variants R243L and R289W. Further studies are needed to validate the association of candidate CAPN5 interactors with proteins and complexes suggested by the SWATH-MS and co-IP results, and the possible role of CAPN5 within such complexes. The possible involvement of CAPN5 in protein quality control is relevant to NIV, as defects in protein quality control have been implicated in inherited retinal disorders. Proteomic data are available via ProteomeXchange with identifier PXD068008. Full article

(This article belongs to the Special Issue Role of Calpains in Health and Diseases)

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18 pages, 7059 KB

Open AccessArticle

VERU-111 Promotes an Anti-Tumor Response Through Restoration of Gut Microbial Homeostasis and Associated Metabolic Dysregulation

by Md Abdullah Al Mamun, Ahmed Rakib, Mousumi Mandal, Wei Li, Duane D. Miller, Hao Chen, Mitzi Nagarkatti, Prakash Nagarkatti and Udai P. Singh

Cells 2026, 15(2), 141; https://doi.org/10.3390/cells15020141 - 13 Jan 2026

Abstract

The rising global burden of colorectal cancer (CRC) has now positioned it as the third most common cancer worldwide. Chemotherapy regimens are known to disrupt the composition of the gut microbiota and lead to long-term health consequences for cancer patients. However, the alteration [...] Read more.

The rising global burden of colorectal cancer (CRC) has now positioned it as the third most common cancer worldwide. Chemotherapy regimens are known to disrupt the composition of the gut microbiota and lead to long-term health consequences for cancer patients. However, the alteration of gut microbiota by specific chemotherapeutic agents has been insufficiently explored until now. The purpose of this study was to assess changes in the gut microbiota following treatment with VERU-111 as a chemotherapy agent for the treatment of CRC. We thus performed a metagenomic study using 16S rRNA gene amplicon sequencing of fecal samples from different experimental groups in the azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced murine model of CRC. To predict the functional potential of microbial communities, we used the resulting 16S rRNA gene sequencing data to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. We found that the administration of VERU-111 led to a restructured microbial community that was characterized by increased alpha and beta diversity. Compared to the mice treated with DSS alone, VERU-111 treatment significantly increased the relative abundance of several bacterial species, including Verrucomicrobiota species, Muribaculum intestinale, Alistipes finegoldii, Turicibacter, and the well-known gut-protective bacterial species Akkermansia muciniphila. The relative abundance of Ruminococcus, which is negatively correlated with immune checkpoint blockade therapy, was diminished following VERU-111 administration. Overall, this metagenomic study suggests that the microbial shift after administration of VERU-111 is associated with suppression of several metabolic and cancer-related pathways that might, at least in part, facilitate the suppression of CRC. These favorable shifts in gut microbiota suggest a novel therapeutic dimension of using VERU-111 to treat CRC and emphasize the need for further mechanistic exploration. Full article

(This article belongs to the Special Issue Identifying Functional Genomics and Pathways in Cancer Pathogenesis and Therapy Resistance)

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29 pages, 809 KB

Open AccessReview

Endocrine Disorders of Calcium Signaling in Children: Neuroendocrine Crosstalk and Clinical Implications

by Roberto Paparella, Francesca Pastore, Lavinia Marchetti, Arianna Bei, Irene Bernabei, Norma Iafrate, Vittorio Maglione, Marcello Niceta, Anna Zambrano, Mauro Celli, Marco Fiore, Ida Pucarelli and Luigi Tarani

Cells 2026, 15(2), 140; https://doi.org/10.3390/cells15020140 - 13 Jan 2026

Abstract

Calcium ions (Ca²⁺) serve as universal second messengers regulating endocrine, neuronal, and metabolic processes. In children and adolescents, tight calcium signaling control is crucial for growth, hormone homeostasis, neuromuscular function, and neurodevelopment. Disruptions in Ca²⁺-dependent pathways—whether genetic, metabolic, or [...] Read more.

Calcium ions (Ca²⁺) serve as universal second messengers regulating endocrine, neuronal, and metabolic processes. In children and adolescents, tight calcium signaling control is crucial for growth, hormone homeostasis, neuromuscular function, and neurodevelopment. Disruptions in Ca²⁺-dependent pathways—whether genetic, metabolic, or acquired—underlie a spectrum of pediatric endocrine diseases often presenting with neurological manifestations This review summarizes calcium’s roles in hormone secretion, parathyroid and vitamin D metabolism, and neuronal excitability, and discusses monogenic and metabolic disorders affecting calcium sensing and signaling, including CASR, GNA11, AP2S1, STIM1, and ORAI1 mutations. Diagnostic challenges, therapeutic strategies, and future directions for precision medicine in pediatric neuroendocrinology are highlighted, emphasizing early recognition and improved clinical outcomes. Full article

(This article belongs to the Special Issue New Discoveries in Calcium Signaling-Related Neurological Disorders)

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28 pages, 14749 KB

Open AccessArticle

Cytosolic Immunostimulatory DNA Ligands and DNA Damage Activate the Integrated Stress Response, Stress Granule Formation, and Cytokine Production

by Trupti Devale, Lekhana Katuri, Gauri Mishra, Aditya Acharya, Praveen Manivannan, Brian R. Hibbard and Krishnamurthy Malathi

Cells 2026, 15(2), 139; https://doi.org/10.3390/cells15020139 - 13 Jan 2026

Abstract

The presence of aberrant double-stranded DNA (dsDNA) in the cytoplasm of cells is sensed by unique pattern recognition receptors (PRRs) to trigger innate immune response. The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway is activated by the presence of non-self [...] Read more.

The presence of aberrant double-stranded DNA (dsDNA) in the cytoplasm of cells is sensed by unique pattern recognition receptors (PRRs) to trigger innate immune response. The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway is activated by the presence of non-self or mislocalized self-dsDNA from nucleus or mitochondria released in response to DNA damage or cellular stress in the cytoplasm. Activation of cGAS leads to the synthesis of the second messenger cyclic GMP–AMP (cGAMP), which binds and activates STING, triggering downstream signaling cascades that result in the production of type I interferons (IFNs) and proinflammatory cytokines. Here, we show that diverse immunostimulatory dsDNA ligands and chemotherapy agents like Doxorubicin and Taxol trigger the integrated stress response (ISR) by activating endoplasmic reticulum (ER) stress kinase, protein kinase RNA-like ER kinase (PERK), in addition to the canonical IFN pathways. PERK-mediated phosphorylation and inactivation of the alpha subunit of eukaryotic translation initiation factor-2 (eIF2α) result in the formation of stress granules (SGs). SG formation by dsDNA was significantly reduced in PERK knockout cells or by inhibiting PERK activity. Transcriptional induction of IFNβ and cytokines, ISR signaling, and SG formation by dsDNA was dampened in cells lacking PERK activity, STING, or key stress-granule nucleating protein, Ras-GAP SH3 domain-binding protein 1 (G3BP1), demonstrating an important role of the signal transduction pathway mediated by STING and SG assembly. Lastly, STING regulates reactive oxygen species (ROS) production in response to DNA damage, highlighting the crosstalk between DNA sensing and oxidative stress pathways. Together, our data identify STING–PERK–G3BP1 signaling axis that couples cytosolic DNA sensing to stress response pathways in maintaining cellular homeostasis. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress Signaling Pathway: From Bench to Bedside)

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21 pages, 4731 KB

Open AccessArticle

Efficiency and Fidelity of Site-Directed Mutagenesis with Complementary Primer Pairs

by Paulina Varela-Castillo, Arezousadat Razavi, Negar Mousavi, Nicole Robinson and Xiang-Jiao Yang

Cells 2026, 15(2), 138; https://doi.org/10.3390/cells15020138 - 13 Jan 2026

Abstract

Based on PCR with complementary primer pairs and Pfu DNA polymerase, QuickChange site-directed mutagenesis has been widely employed, but its efficiency varies from mutation to mutation. An alternative strategy relies on partially overlapping primer pairs with 3′-overhangs, and this strategy has led to [...] Read more.

Based on PCR with complementary primer pairs and Pfu DNA polymerase, QuickChange site-directed mutagenesis has been widely employed, but its efficiency varies from mutation to mutation. An alternative strategy relies on partially overlapping primer pairs with 3′-overhangs, and this strategy has led to the recent development of P3a and P3b site-directed mutagenesis, in which the use of SuperFi II and Q5 polymerases raises the mutagenesis efficiency to ~100%. It is unclear whether these two DNA polymerases also improve the QuickChange method. Herein, we have evaluated this possibility by engineering 46 mutations on seven expression plasmids, two of which possess extremely GC-rich sequences. As Pfu DNA polymerase is a slow enzyme, its replacement with SuperFi II and Q5 polymerases reduced PCR length. Moreover, the average efficiency for each of the seven plasmids ranged from 48% to 69%, thereby outperforming the original QuickChange method. However, this efficiency is still lower than that from the P3a and P3b methods, supporting the superiority of primer pairs with 3′-overhangs. Analysis of the incorrect plasmids from the improved QuickChange method revealed frequent insertions at primer sites. The insertions were derived from primers and varied from mutation to mutation, with certain sites much more prone to such insertions. In comparison, these insertions occurred at a much lower frequency with the P3a and P3b methods, suggesting that primer pairs with 3′-overhangs enhance mutagenesis efficiency by reducing the likelihood to introduce insertions at primer sites. Thus, this study improves the QuickChange mutagenesis method, supports the superiority of the P3a and P3b methods, and uncovers a novel molecular mechanism by which the efficiency of PCR-based mutagenesis with completely overlapping primer pairs is negatively affected. Full article

(This article belongs to the Section Cell Methods)

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24 pages, 17045 KB

Open AccessArticle

BAP31 Modulates Mitochondrial Homeostasis Through PINK1/Parkin Pathway in MPTP Parkinsonism Mouse Models

by Wanting Zhang, Shihao Meng, Zhenzhen Hao, Xiaoshuang Zhu, Lingwei Cao, Qing Yuan and Bing Wang

Cells 2026, 15(2), 137; https://doi.org/10.3390/cells15020137 - 12 Jan 2026

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by age-dependent degeneration of dopaminergic neurons in the substantia nigra, a process mediated by α-synuclein aggregation, mitochondrial dysfunction, and impaired proteostasis. While BAP31—an endoplasmic reticulum protein critical for protein trafficking and degradation—has been implicated in [...] Read more.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by age-dependent degeneration of dopaminergic neurons in the substantia nigra, a process mediated by α-synuclein aggregation, mitochondrial dysfunction, and impaired proteostasis. While BAP31—an endoplasmic reticulum protein critical for protein trafficking and degradation—has been implicated in neuronal processes, its role in PD pathogenesis remains poorly understood. To investigate the impact of BAP31 deficiency on PD progression, we generated dopamine neuron-specific BAP31 conditional knockout with DAT-Cre (cKO) mice (Slc6a3cre-BAP31^fl/fl) and subjected them to MPTP-lesioned Parkinsonian models. Compared to BAP31^fl/fl controls, Slc6a3cre-BAP31^fl/fl mice exhibited exacerbated motor deficits following MPTP treatment, including impaired rotarod performance, reduced balance beam traversal time, and diminished climbing and voluntary motor capacity abilities. BAP31 conditional deletion showed no baseline phenotype, with deficits emerging only after MPTP. Our results indicate that these behavioral impairments correlated with neuropathological hallmarks: decreased NeuN neuronal counts, elevated GFAP astrogliosis, reduced tyrosine hydroxylase levels in the substantia nigra, and aggravated dopaminergic neurodegeneration. Mechanistically, BAP31 deficiency disrupted mitochondrial homeostasis by suppressing the PINK1–Parkin mitophagy pathway. Further analysis revealed that BAP31 regulates PINK1 transcription via the transcription factor Engrailed Homeobox 1. Collectively, our findings identify BAP31 as a neuroprotective modulator that mitigates PD-associated motor dysfunction by preserving mitochondrial stability, underscoring its therapeutic potential as a target for neurodegenerative disorders. Full article

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32 pages, 1112 KB

Open AccessReview

Microbial Modulation: Unraveling the Influence of Gut Microbiota on Macrophage Polarization in Tumor Microenvironments

by Jonathan Trejo, Hayes Koegeboehn, Farah Faizuddin, Ryan Logan, Michel Toutoungy, Aadil Sheikh, Tamer E. Fandy, Sergio Saucedo, Victor M. Vasquez, Jr., Thien Nguyen, Jennifer T. Grier, Ghislaine Mayer and Jessica Chacon

Cells 2026, 15(2), 136; https://doi.org/10.3390/cells15020136 - 12 Jan 2026

Abstract

The intricate interplay between the human microbiota and the immune system has garnered significant attention in recent years, particularly concerning its implications in cancer biology. Macrophages, pivotal players in the tumor microenvironment (TME), exhibit diverse phenotypes that can either promote tumor progression or [...] Read more.

The intricate interplay between the human microbiota and the immune system has garnered significant attention in recent years, particularly concerning its implications in cancer biology. Macrophages, pivotal players in the tumor microenvironment (TME), exhibit diverse phenotypes that can either promote tumor progression or inhibit it. This review explores the multifaceted role of the microbiota in modulating macrophage polarization within the TME. We highlight recent findings that demonstrate how specific microbial communities influence macrophage behavior through metabolic pathways, immune signaling, and epigenetic modifications. Furthermore, we discuss the therapeutic potential of manipulating the microbiota to reprogram macrophage phenotypes, thereby enhancing antitumor immunity. By integrating insights from microbiology, immunology, and oncology, this article aims to provide a comprehensive overview of the microbiota’s impact on macrophage dynamics in cancer, paving the way for innovative therapeutic strategies that harness this relationship for improved clinical outcomes. Full article

(This article belongs to the Special Issue Macrophages in Cancer: Immunosuppression, Immunoregulation, and Immunotherapy)

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