Cells

25 pages, 7655 KB

Open AccessArticle

Pancreatic Cancer Stem Cells Co-Expressing SOX2, OCT4, and TERT^high Represent an Aggressive Subpopulation

by Erika Curiel-Gomez, Damaris P. Romero-Rodriguez, Mauricio Rodriguez-Dorantes, Vilma Maldonado and Jorge Melendez-Zajgla

Cells 2026, 15(2), 129; https://doi.org/10.3390/cells15020129 (registering DOI) - 11 Jan 2026

Abstract

The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) has been linked to cancer stem cells (CSCs) and telomerase activity; however, the mechanism underlying this association remains unclear. In this study, we engineered dual transcriptional reporters (SORE6-GFP and TERT-BFP) to isolate SOX2⁺OCT4⁺ [...] Read more.

The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) has been linked to cancer stem cells (CSCs) and telomerase activity; however, the mechanism underlying this association remains unclear. In this study, we engineered dual transcriptional reporters (SORE6-GFP and TERT-BFP) to isolate SOX2⁺OCT4⁺TERT^high subpopulations from AsPC-1 and BxPC-3 cells. We combined Fluorescence-Activated Cell Sorting with functional assays, RNA-seq, and network analysis. Clinically, tumors co-expressing high SOX2/OCT4/TERT levels were associated with reduced overall survival, whereas single-gene elevations were not prognostic. We identified a minority SOX2⁺OCT4⁺TERT^high fraction (~9%) enriched for pluripotency transcripts (SOX2, OCT4, NANOG, and ALDH1A1), which exhibited the highest proliferative, migratory, and invasive capacities. Transcriptomic profiling of SOX2⁺OCT4⁺TERT^high cells showed enrichment of KRAS, telomere maintenance, epithelial–mesenchymal transition, and developmental pathways (WNT and Hedgehog). Connectivity profiling highlighted actionable vulnerabilities, including NF-κB, WNT, and telomerase inhibition pathways. Together, these data define an aggressive telomerase-engaged, pluripotency-driven CSC-like state in PDAC and suggest testable therapeutic strategies that target TERT^high dependencies. Full article

(This article belongs to the Special Issue Signal Transduction and Targeted Therapy for Tumors)

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17 pages, 580 KB

Open AccessReview

MHC Class II and Beyond: Complex Role of CD74 in Cancer

by Joanna Bandola-Simon and Paul A. Roche

Cells 2026, 15(2), 128; https://doi.org/10.3390/cells15020128 (registering DOI) - 11 Jan 2026

Abstract

Invariant chain, also known as CD74 when expressed on the plasma membrane, is classically recognized for its role in Major Histocompatibility Complex class II molecule assembly, trafficking, and peptide loading in professional antigen presenting cells. However, recent studies implicate CD74 as a broader [...] Read more.

Invariant chain, also known as CD74 when expressed on the plasma membrane, is classically recognized for its role in Major Histocompatibility Complex class II molecule assembly, trafficking, and peptide loading in professional antigen presenting cells. However, recent studies implicate CD74 as a broader regulator of tumor–immune interactions, modulating antigen presentation, cytokine signaling, and immune evasion across diverse cancers. This review synthesizes emerging evidence that CD74 functions as a “master regulator” of antigen presentation in cancer, integrating its canonical chaperone role with its noncanonical role in transcription regulation and in signaling via macrophage migration inhibitory factor. We explore how tumor microenvironmental contexts redefine CD74 biology, influencing antitumor immunity and therapeutic outcomes. Full article

(This article belongs to the Special Issue Antigen Processing in Autoimmunity and Cancer—Mechanisms and Translational Perspectives)

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16 pages, 1760 KB

Open AccessArticle

Targeting of Human Mitochondrial DNA with Programmable pAgo Nuclease

by Beatrisa Rimskaya, Ekaterina Kropocheva, Elza Shchukina, Egor Ulashchik, Daria Gelfenbein, Lidiya Lisitskaya, Vadim Shmanai, Svetlana Smirnikhina, Andrey Kulbachinskiy and Ilya Mazunin

Cells 2026, 15(2), 127; https://doi.org/10.3390/cells15020127 (registering DOI) - 10 Jan 2026

Abstract

Manipulating the mitochondrial genome remains a significant challenge in genetic engineering, primarily due to the mitochondrial double-membrane structure. While recent advances have expanded the genetic toolkit for nuclear and cytoplasmic targets, precise editing of mitochondrial DNA (mtDNA) has remained elusive. Here we report [...] Read more.

Manipulating the mitochondrial genome remains a significant challenge in genetic engineering, primarily due to the mitochondrial double-membrane structure. While recent advances have expanded the genetic toolkit for nuclear and cytoplasmic targets, precise editing of mitochondrial DNA (mtDNA) has remained elusive. Here we report the first successful mitochondrial import of a catalytically active RNA-guided prokaryotic Argonaute protein from the mesophilic bacterium Alteromonas macleodii (AmAgo). By guiding AmAgo to the single-stranded D- or R-loop region of mtDNA using synthetic RNA guides, we observed a nearly threefold reduction in mtDNA copy number in human cell lines. This proof of concept study demonstrates that a bacterial Argonaute can remain active within the mitochondrial environment and influence mtDNA levels. These findings establish a foundational framework for further development of programmable systems for mitochondrial genome manipulation. Full article

(This article belongs to the Special Issue Mitochondria at the Crossroad of Health and Disease—Second Edition)

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22 pages, 5690 KB

Open AccessArticle

Cancer Immunomodulatory Effect of Bidens pilosa L. in Mice: Suppression of Tumor-Associated Macrophages and Regulatory T Cells

by Meihua Zhu, Jiayan Xiong, Ruyi Zhang, Xingyan Yang, Weiqing Sun, Ziyi Yang, Yuhan Chai, Yang Tao, Yu-Qiang Zhao, Baomin Fan and Guangzhi Zeng

Cells 2026, 15(2), 126; https://doi.org/10.3390/cells15020126 (registering DOI) - 10 Jan 2026

Abstract

Bidens pilosa L., a traditional Chinese medicinal herb, has been used in clinical practice for the treatment of inflammatory diseases and cancer. BPA, an extract derived from the whole herb of B. pilosa L., has been shown to possess potent immunomodulatory properties [...] Read more.

Bidens pilosa L., a traditional Chinese medicinal herb, has been used in clinical practice for the treatment of inflammatory diseases and cancer. BPA, an extract derived from the whole herb of B. pilosa L., has been shown to possess potent immunomodulatory properties by regulating tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) within the tumor microenvironment (TME) in a mouse syngeneic colorectal cancer (CRC) model. RT-PCR and flow cytometry analyses showed that BPA, together with its flavonoid and polyacetylene constituents, effectively suppressed the differentiation of M2-TAMs and Tregs by downregulating Arg-1 and CD25 expression. They had minimal effects on the expression of markers associated with M1-TAMs and promoted the proliferation of CD4⁺ T cells that were inhibited by M2-TAMs and Tregs. In mice, BPA markedly inhibited the growth of syngeneic CRC tumors, accompanied by decreased serum levels of the immunosuppressive cytokine IL-10 and reduced expression of the proliferative marker Ki67 in tumor tissues. Moreover, BPA downregulated the mRNA expression of markers associated with M2-TAMs and Tregs, while increasing markers associated with M1-TAMs. Western blot analyses of tumor tissues revealed that BPA reduced the expression of marker proteins associated with M2-TAMs and Tregs, while increasing the expression of the immune-stimulatory markers CD80, GITR and CD4. In addition, combined treatment with BPA and 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent for CRC, notably enhanced the anti-tumor effect in mice. These findings indicate that BPA, an active extract of B. pilosa L., showed antitumor activity in mice by suppressing the differentiation of pro-tumorigenic TAMs and Tregs within the TME. Full article

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16 pages, 2207 KB

Open AccessArticle

Establishment of Patient-Derived Organoids from Hepatocellular Carcinoma: Preliminary Data on Yield, Histopathological Concordance, and Methodological Challenges

by Oriana Lo Re, Christian Corti, Lucia Cerrito, Eleonora Cesari, Elisabetta Creta, Flavio De Maio, Alessia Di Prima, Vincenzo Facciuto, Clelia Ferraro, Eleonora Huqi, Rosa Liotta, Margot Lo Pinto, Duilio Pagano, Riccardo Perriera, Valentina Petito, Giulia Santarelli, Francesco Santopaolo, Leonardo Stella, Floriana Tortomasi, Claudio Sette, Salvatore Gruttadauria, Felice Giuliante, Giovanni Zito and Francesca Romana Ponziani Show full author list Hide full author list

Cells 2026, 15(2), 125; https://doi.org/10.3390/cells15020125 (registering DOI) - 10 Jan 2026

Abstract

Patient-derived organoids (PDOs) have emerged as promising preclinical models for studying tumor biology and testing therapeutic strategies in oncology. These three-dimensional culture systems retain key histological, genetic, and functional characteristics of the original tumors, offering a unique opportunity to advance personalized medicine approaches [...] Read more.

Patient-derived organoids (PDOs) have emerged as promising preclinical models for studying tumor biology and testing therapeutic strategies in oncology. These three-dimensional culture systems retain key histological, genetic, and functional characteristics of the original tumors, offering a unique opportunity to advance personalized medicine approaches in liver cancer. In this study, we present the methodological framework and preliminary findings of a prospective study aimed at generating and characterizing PDOs from patients with hepatocellular carcinoma (HCC) undergoing surgical resection. Tumor specimens were processed using an optimized protocol for organoid derivation, expansion, and cryopreservation. We evaluated the success rate of organoid establishment and the histo-molecular fidelity to the parental tumor. These early results demonstrate promising engraftment efficiency and maintenance of tumor-specific markers across passages. Our work highlights the potential of PDOs as a reliable and scalable platform for translational research in HCC, setting the stage for future applications in drug screening and biomarker discovery. Full article

(This article belongs to the Section Tissues and Organs)

22 pages, 2430 KB

Open AccessArticle

Estrogen-Induced Hypermethylation Silencing of RPS2 and TMEM177 Inhibits Energy Metabolism and Reduces the Survival of CRC Cells

by Batoul Abi Zamer, Bilal Rah, Wafaa Abumustafa, Zheng-Guo Cui, Mawieh Hamad and Jibran Sualeh Muhammad

Cells 2026, 15(2), 124; https://doi.org/10.3390/cells15020124 (registering DOI) - 9 Jan 2026

Abstract

Estrogen (E2, 17β estradiol) is recognized for its regulatory role in numerous genes associated with energy metabolism and for its ability to disrupt mitochondrial function in various cancer types. However, the influence of E2 on the metabolism of colorectal cancer (CRC) cells remains [...] Read more.

Estrogen (E2, 17β estradiol) is recognized for its regulatory role in numerous genes associated with energy metabolism and for its ability to disrupt mitochondrial function in various cancer types. However, the influence of E2 on the metabolism of colorectal cancer (CRC) cells remains largely unexplored. In this study, we examined how E2 affects mitochondrial function and energy production in CRC cells, utilizing two distinct CRC cell lines, HCT-116 and SW480. Cell viability, mitochondrial function, and the expression of several genes involved in oxidative phosphorylation (OXPHOS) were assessed in estrogen receptor α (ERα)-expressing and ERα-silenced cells treated with increasing concentrations of E2 for 48 h. Our results indicated that the cytotoxicity of E2 against CRC cells is mediated by the E2/ERα complex, which induces disturbances in mitochondrial function and the OXPHOS pathway. Furthermore, we identified two novel targets, RPS2 and TMEM177, which displayed overexpression, hypomethylation, and a negative association with ERα expression in CRC tissue. E2 treatment in CRC cells reduced the expression of both targets through promoter hypermethylation. Treatment with 5-Aza-2-deoxycytidine increased the expression of RPS2 and TMEM177. This epigenetic effect disrupts the mitochondrial membrane potential (MMP), resulting in decreased activity of the OXPHOS pathway and inhibition of CRC cell growth. Knockdown of RPS2 or TMEM177 in CRC cells resulted in anti-cancer effects and disruption of MMP and OXPHOS. These findings suggest that E2 exerts ERα-dependent epigenetic reprogramming that leads to significant mitochondria-related anti-growth effects in CRC. Full article

(This article belongs to the Special Issue Cellular Metabolism and Hormonal Signaling in Colorectal Cancer: Biomarkers and Therapeutic Opportunities)

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20 pages, 1019 KB

Open AccessArticle

A Novel ALDH2 Inhibitor for the Treatment of Alcohol Use Disorder: Preclinical Findings

by Randall D. Marshall, Andrew Fowlie and Adam Sabouni

Cells 2026, 15(2), 123; https://doi.org/10.3390/cells15020123 (registering DOI) - 9 Jan 2026

Abstract

Background: Alcohol use disorder is a common condition with high morbidity and mortality and no highly effective treatments. Achieving and maintaining abstinence is necessary or desired for many persons with AUD, but is difficult due to the nature of the condition. Pharmacologic inhibition [...] Read more.

Background: Alcohol use disorder is a common condition with high morbidity and mortality and no highly effective treatments. Achieving and maintaining abstinence is necessary or desired for many persons with AUD, but is difficult due to the nature of the condition. Pharmacologic inhibition of the enzyme ALDH2, which increases levels of the substrate acetaldehyde when alcohol is imbibed, can serve as a powerful enforcer of efforts to remain abstinent. Disulfiram is an approved ALDH2 inhibitor via its active metabolite DETC-MeSO, but has many limitations, including numerous adverse effects, hepatotoxicity, oral administration, and unpredictable mechanistic activity. Methods: SOPH-110S, an analog of DETC-MeSO, was evaluated in a series of experiments to assess mechanism, pharmacokinetics in male beagle dogs, cardiovascular safety in telemeterized male beagle dogs, selectivity, off-target activity, CYP inhibition, and proof of mechanism in a rat model that included dosing and alcohol challenge followed by analysis of liver ALDH2 inhibition. Results: SOPH-110S showed high potency with a comparable IC₅₀ vs. positive controls and no physiologically relevant off-target binding in an 84-target panel. It did not inhibit or induce any major CYP enzymes or meaningfully inhibit the hERG channel. After 10 days’ dosing in rats, followed by administration of alcohol, SOPH-110S was a highly potent, dose-dependent inhibitor of ALDH2, comparable to DETC-MeSO. No cardiovascular safety concerns were found at multiples above expected clinical doses. Conclusions: The preclinical data support further clinical study of SOPH-110S as a potential ALDH2 inhibitor treatment for AUD. The FDA approved the IND to conduct a first-in-man phase 1 study in September 2025. Full article

(This article belongs to the Special Issue Biological Mechanisms in the Treatment of Neuropsychiatric Diseases)

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21 pages, 3384 KB

Open AccessArticle

Diabetes Alters microRNA Expression in Epicardial and Subcutaneous Adipose Tissue from Patients Undergoing Elective Cardiac Surgery

by Diana Santos, António Canotilho, Gonçalo Coutinho, David Prieto, Pedro Antunes, Manuel Antunes, Adelino F. Leite Moreira, Inês Falcão-Pires, Eugenia Carvalho and Louise Torp Dalgaard

Cells 2026, 15(2), 122; https://doi.org/10.3390/cells15020122 - 9 Jan 2026

Abstract

Epicardial adipose tissue (EAT) function may influence the heart, given its metabolic actions and proximity to the heart. We hypothesized that diabetes mellitus (DM) alters miRNA expression across adipose tissue types, and that modifications in EAT may have critical implications for cardiac physiology. [...] Read more.

Epicardial adipose tissue (EAT) function may influence the heart, given its metabolic actions and proximity to the heart. We hypothesized that diabetes mellitus (DM) alters miRNA expression across adipose tissue types, and that modifications in EAT may have critical implications for cardiac physiology. To test this, we compared EAT and subcutaneous adipose tissue (SAT) miRNA profiles between patients with and without DM and across tissues within each disease group. Paired biopsies from patients with (n = 18) and without DM (n = 46) undergoing cardiac surgery were analyzed using miRNA profiling and bioinformatics. Among 680 miRNAs screened, 34 were uniquely expressed in EAT, confirming a distinct molecular signature in this fat depot. Notably, miR-155-5p was significantly elevated in EAT from patients with DM, indicating a localized metabolic effect. In SAT, miR-93-3p and miR-223-3p were upregulated in patients with DM and consistently higher than in EAT, regardless of DM status, indicating tissue-specific regulation. miR-324-5p was more expressed in SAT of patients in the NDM group, reflecting combined effects of tissue type and DM. These patterns remained consistent across cardiac disease stratifications. Pathway analysis revealed that miRNAs enriched in EAT target genes involved in cardiomyocyte growth and differentiation. Overall, the findings highlight the unique miRNA profile of epicardial fat and its altered response to DM, supporting its relevance in cardiac physiology. Full article

36 pages, 1741 KB

Open AccessReview

Extracellular Vesicles as Biological Templates for Next-Generation Drug-Coated Cardiovascular Devices: Cellular Mechanisms of Vascular Healing, Inflammation, and Restenosis

by Rasit Dinc and Nurittin Ardic

Cells 2026, 15(2), 121; https://doi.org/10.3390/cells15020121 (registering DOI) - 9 Jan 2026

Abstract

While drug-eluting cardiovascular devices, including drug-eluting stents and drug-coated balloons, have significantly reduced restenosis rates, they remain limited by delayed vascular healing, chronic inflammation, and late adverse events. These limitations reflect a fundamental mismatch between current device pharmacology, which relies on nonselective antiproliferative [...] Read more.

While drug-eluting cardiovascular devices, including drug-eluting stents and drug-coated balloons, have significantly reduced restenosis rates, they remain limited by delayed vascular healing, chronic inflammation, and late adverse events. These limitations reflect a fundamental mismatch between current device pharmacology, which relies on nonselective antiproliferative drugs, and the highly coordinated, cell-specific programs that orchestrate vascular repair. Extracellular vesicles (EVs), nanometer-scale membrane-bound particles secreted by virtually all cell types, provide a biologically evolved platform for intercellular communication and cargo delivery. In the cardiovascular system, EVs regulate endothelial regeneration, smooth muscle cell phenotype, extracellular matrix remodeling, and macrophage polarization through precisely orchestrated combinations of miRNA, proteins, and lipids. Here, we synthesize mechanistic insights into EV biogenesis, cargo selection, recruitment, and functional effects in vascular healing and inflammation and translate these into a formal framework for EV-inspired device engineering. We discuss how EV-based or EV-mimetic coatings can be designed to sense the local microenvironment, deliver encoded biological “instruction sets,” and function within ECM-mimetic scaffolds to couple local stent healing with systemic tissue repair. Finally, we outline the manufacturing, regulatory, and clinical trial issues that must be addressed for EV-inspired cardiovascular devices to transition from proof of concept to clinical reality. By shifting the focus from pharmacological suppression to biological regulation of healing, EV-based strategies offer a path to resolve the long-standing tradeoff between restenosis prevention and durable vascular healing. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Repair and Regeneration)

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17 pages, 2667 KB

Open AccessArticle

Topical CCL3 Is Well-Tolerated and Improves Liver Function in Diabetic Mice: Evidence from a 14-Day Toxicity Study

by Deepa Dehari, Rajalekshmy Padmakumari, Getnet Tesfaw, Fernando A. Fierro, Guillermo A. Ameer and Sasha H. Shafikhani

Cells 2026, 15(2), 120; https://doi.org/10.3390/cells15020120 - 9 Jan 2026

Abstract

Diabetic wounds exhibit impaired immune function, delayed neutrophils recruitment, and heightened infection risk which compromises early infection control and delays healing. We have demonstrated that topical CCL3 treatment restores neutrophil influx, reduces bacterial infection by ~99%, and accelerates wound healing in diabetic mice. [...] Read more.

Diabetic wounds exhibit impaired immune function, delayed neutrophils recruitment, and heightened infection risk which compromises early infection control and delays healing. We have demonstrated that topical CCL3 treatment restores neutrophil influx, reduces bacterial infection by ~99%, and accelerates wound healing in diabetic mice. As per Food and Drug Administration (FDA) Guidelines for Investigational New Drug (IND), we conducted a 14-day acute toxicity study in diabetic mice following a single topical administration of CCL3 at effective low dose (1 µg) and high dose (10 µg) per wound. Mice were monitored for clinical signs, body weight, and food intake throughout the study period. On day 14, serum biochemistry (ALT, AST, BUN, creatinine, metabolic markers) and histopathology of major organs (liver, kidney, heart, lungs, spleen) were assessed. CCL3-treated diabetic mice exhibited no adverse clinical effects. Hematological and biochemical parameters remained within normal limits, and histopathological analyses revealed no additional organ injury in CCL3-treated groups compared to diabetic control mice. Intriguingly, CCL3-treated mice showed improved ALT levels and reduced hepatic pathology, suggesting hepatoprotective effects and reduced serum IgG, indicating reduced systemic inflammation. Overall, our study demonstrates that diabetic mice tolerate topical CCL3 at doses up to 10 times the effective therapeutic concentration without evidence of systemic organ toxicity. These findings provide strong preclinical support for the translational development of CCL3 as a novel therapy for diabetic wound care. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Repair)

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25 pages, 2792 KB

Open AccessReview

B-Cells and Plasmablasts as Architects of Autoimmune Disease: From Molecular Footprints to Precision Therapeutics

by Julie Sarrand and Muhammad Soyfoo

Cells 2026, 15(2), 119; https://doi.org/10.3390/cells15020119 - 9 Jan 2026

Abstract

B-cells and plasmablasts have emerged as central organizers of autoimmune pathogenesis, extending far beyond their classical role as antibody-producing cells to orchestrate immune circuits, tissue microenvironments, and therapeutic trajectories. Advances in single-cell technologies, high-dimensional cytometry, and B-cell receptor sequencing have uncovered a dynamic [...] Read more.

B-cells and plasmablasts have emerged as central organizers of autoimmune pathogenesis, extending far beyond their classical role as antibody-producing cells to orchestrate immune circuits, tissue microenvironments, and therapeutic trajectories. Advances in single-cell technologies, high-dimensional cytometry, and B-cell receptor sequencing have uncovered a dynamic continuum of B-cell differentiation programs that drive clinical heterogeneity across systemic autoimmune diseases. Plasmablasts, in particular, have gained recognition as highly responsive sensors of immune activation: they expand during flares, encode interferon-driven and extrafollicular responses, and correlate with disease severity. Autoantibody profiles, long viewed as static diagnostic signatures, are now understood as durable molecular footprints of distinct B-cell pathways. In this review, we propose an endotype-based framework integrating B-cell circuits with clinical phenotypes, illustrate therapeutic decision-making through mechanistic case vignettes, and outline future strategies combining immunomonitoring, multi-omics, and precision therapeutics. We further address translational challenges and discuss complementary approaches, including T-cell modulation, FcRn inhibition, and antigen-specific tolerization. Full article

(This article belongs to the Special Issue Advances in Cellular and Molecular Treatment of Autoimmune Diseases—Second Edition)

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12 pages, 2182 KB

Open AccessCommunication

BRD4 Phosphorylation Regulates the Structure of Chromatin Nanodomains

by Clayton Seitz, Donghong Fu, Mengyuan Liu, Hailan Ma and Jing Liu

Cells 2026, 15(2), 118; https://doi.org/10.3390/cells15020118 - 9 Jan 2026

Abstract

The interplay between chromatin structure and phase-separating proteins is an emerging topic in cell biology with implications for understanding disease states. Here, we investigate the functional relationship between bromodomain protein 4 (BRD4) and chromatin architecture. By combining molecular dynamics simulations with live-cell imaging, [...] Read more.

The interplay between chromatin structure and phase-separating proteins is an emerging topic in cell biology with implications for understanding disease states. Here, we investigate the functional relationship between bromodomain protein 4 (BRD4) and chromatin architecture. By combining molecular dynamics simulations with live-cell imaging, we demonstrate that BRD4, when mutated at specific N-terminus sites, significantly impacts the organization and dynamics of chromatin nanodomains, known as nucleosome clutches. Our findings reveal that a constitutively phosphorylated mutant of BRD4 condenses nucleosome clutches, while treatment with (+)-JQ1 increases the diffusion dynamics of single nucleosomes and decondenses nucleosome clutches. Simultaneously, we demonstrate that BRD4 mutations can alter localization of BRD4 to chromatin as well as modify single nucleosome dynamics. These results suggest that both chromatin binding and phase separation of BRD4 could co-regulate the nanoscale chromatin architecture and the chromatin microenvironment. Our observations shed light on the nuanced regulation of chromatin structure by BRD4, offering insights into its role in maintaining the nuclear architecture and transcriptional activity. Full article

(This article belongs to the Section Cellular Biophysics)

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20 pages, 3144 KB

Open AccessCommunication

miR-204 Negatively Regulates HIV-Tat-Mediated Inflammation in Cervical Epithelial Cells via the NF-κB Axis: Insights from an In Vitro Study

by Kadambari Akolkar and Vandana Saxena

Cells 2026, 15(2), 117; https://doi.org/10.3390/cells15020117 - 9 Jan 2026

Abstract

Despite antiretroviral therapy, HIV proteins, such as Tat, persist in tissues, driving chronic inflammation. Cervical inflammation in females not only accelerates HIV progression but also increases the risk of other STIs; hence, understanding the underlying factors/regulators is vital. However, Tat-induced cervical inflammation and [...] Read more.

Despite antiretroviral therapy, HIV proteins, such as Tat, persist in tissues, driving chronic inflammation. Cervical inflammation in females not only accelerates HIV progression but also increases the risk of other STIs; hence, understanding the underlying factors/regulators is vital. However, Tat-induced cervical inflammation and its regulation are hitherto poorly understood, which we investigated using TZM-bl cells. Tat stimulation in these cervical epithelial cells significantly increased the expression of various inflammatory mediators, including cytokines (IL-1β, TNF-α, IL-6, IL-17a, GM-CSF), chemokines (MIP-1α, MIP-1β), adhesion molecules (ICAM-1, P-Selectin, E-Selectin), and ROS. Further upregulation of inflammatory mediators (NF-κB, IRAK-4) along with TLR7 was observed in Tat-stimulated cells. Interestingly, Tat stimulation decreased miR-204-5p expression in these cells, suggesting a role in regulating Tat-mediated inflammatory processes. Using a gain-of-function approach, we further observed that the overexpression of miR-204-5p reduced the expression of IL-1β, TNF-α, IL-6, MIP-1α, MIP-1β, ICAM-1, P-Selectin, and ROS in the Tat-stimulated TZM-bl cells, along with NF-κB, IRAK-1, and IRAK-4. Using Western blotting and luciferase assays, miR-204-5p was further shown to directly target NF-κB. Here, we report that HIV-1 Tat stimulation in cervical epithelial cells downregulates hsa-miR-204-5p, thereby activating the pro-inflammatory TLR7/NF-κB axis, highlighting its relevance to understanding mechanisms underlying cervical inflammation. Full article

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20 pages, 6255 KB

Open AccessArticle

Separate BNST Microcircuits Targeted by Direct Versus Amygdala-Relayed Prefrontal Inputs Mediate Dissociable Phenotypes After Isolation

by Hongxia Yuan, Yongmei Zhong and Xuehan Zhang

Cells 2026, 15(2), 116; https://doi.org/10.3390/cells15020116 - 8 Jan 2026

Abstract

Anxiety, depression, and social impairment exhibit high clinical comorbidity, yet their underlying shared neural circuitry remains poorly defined. Using a mouse model of chronic social isolation combined with circuit tracing and chemogenetic tools, we identified a key role for the basolateral amygdala (BLA) [...] Read more.

Anxiety, depression, and social impairment exhibit high clinical comorbidity, yet their underlying shared neural circuitry remains poorly defined. Using a mouse model of chronic social isolation combined with circuit tracing and chemogenetic tools, we identified a key role for the basolateral amygdala (BLA) in relaying prefrontal cortex (PFC) signals to the bed nucleus of the stria terminalis (BNST) to drive behavioral changes. Further circuit dissection identified two distinct BNST microcircuits segregated by their input sources: one receives indirect PFC input relayed through the BLA (PFC → BLA → BNST), while the other is innervated by direct PFC projections (PFC → BNST). Chemogenetic inhibition of BLA neurons in the indirect pathway ameliorated anxiety-like behavior, depression-like behavior, and social deficits. Within the BNST, however, inhibition of neurons in PFC → BLA → BNST pathway selectively alleviated affective phenotypes without altering social behavior. In contrast, inhibition of neurons in PFC → BNST pathway specifically restored social recognition while leaving emotional behaviors intact. Thus, the BLA integrates PFC-derived signals to broadly modulate behavior, while downstream BNST microcircuits dissociate these influences. The indirect, BLA-relayed pathway within the BNST specifically drives affective symptoms, whereas the direct PFC → BNST pathway selectively governs social recognition. This dissociable circuit model offers a new framework for understanding clinical comorbidity and may inform targeted interventions for distinct symptom dimensions. Full article

(This article belongs to the Special Issue Recent Advances in the Understanding of Neuropsychiatric Illnesses)

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28 pages, 13608 KB

Open AccessArticle

Single-Cell Transcriptomic Landscape of Cervical Cancer Cell Lines Before and After Chemoradiotherapy

by Dmitriy V. Semenov, Irina S. Tatarnikova, Anna S. Chesnokova, Vadim A. Talyshev, Marina A. Zenkova and Evgeniya B. Logashenko

Cells 2026, 15(2), 115; https://doi.org/10.3390/cells15020115 - 8 Jan 2026

Abstract

Cervical cancer remains a significant global health burden, with chemoradioresistance representing a major obstacle to successful treatment. To elucidate the mechanisms underlying this resistance, we established a unique pair of isogenic primary cervical cancer cell lines, AdMer35 and AdMer43, obtained from a patient [...] Read more.

Cervical cancer remains a significant global health burden, with chemoradioresistance representing a major obstacle to successful treatment. To elucidate the mechanisms underlying this resistance, we established a unique pair of isogenic primary cervical cancer cell lines, AdMer35 and AdMer43, obtained from a patient with squamous cell carcinoma of the cervix before and after radiation therapy. The aim of our study was to characterize the transcriptomic and cellular heterogeneity of these cells. We conducted an in-depth comparative analysis using single-cell RNA sequencing. Analysis of this paired, patient-derived isogenic model suggests that chemoradioresistance can arise through coordinated multilevel cellular adaptations. Resistant AdMer43 cells demonstrated transcriptional reprogramming, with the upregulation of embryonic stemness factors (HOX, POU5F1, SOX2), a shift in extracellular matrix from fibrillar to non-fibrillar collagens, and activation of inflammatory pathways. We identified and characterized critical cell-state dynamics: resistant cells exhibited a remodeled ecosystem with a metabolically reprogrammed senescent-like cell population showing an enhanced pro-tumorigenic communication via EREG, SEMA3C, BMP, and WNT pathways. Furthermore, we identified a progenitor-like cell population with a minimal CNV burden, potentially serving as a reservoir for tumor persistence. These findings offer novel insights for developing targeted strategies to eliminate resistant cell pools and improve cervical cancer outcomes. Full article

(This article belongs to the Special Issue Advances in Molecular Genomics and Pathology of Cancers)

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23 pages, 1108 KB

Open AccessReview

Senescence as a Driver of Smooth Muscle Cell Plasticity and Atherosclerosis: Mechanisms and Therapeutic Opportunities

by Lisa Steegen and Mandy O. J. Grootaert

Cells 2026, 15(2), 114; https://doi.org/10.3390/cells15020114 - 8 Jan 2026

Abstract

Cell senescence is increasingly recognized as a key driver of atherosclerosis progression. Senescent smooth muscle cells (SMCs) lose their proliferative capacity and adopt a pro-inflammatory profile, contributing to impaired vessel repair and weakening of the fibrous cap. Moreover, senescence promotes SMC dedifferentiation and [...] Read more.

Cell senescence is increasingly recognized as a key driver of atherosclerosis progression. Senescent smooth muscle cells (SMCs) lose their proliferative capacity and adopt a pro-inflammatory profile, contributing to impaired vessel repair and weakening of the fibrous cap. Moreover, senescence promotes SMC dedifferentiation and phenotypic modulation into unfavorable phenotypes associated with plaque destabilization. In this review, we will discuss how cell senescence is induced in atherosclerotic plaques, how this influences SMC plasticity, and how this impacts plaque stability. We will also evaluate the potential of current and experimental anti-atherosclerotic drugs to target SMC senescence and/or SMC phenotypic modulation. Full article

(This article belongs to the Special Issue Emerging Topics in Smooth Muscle Cell Fate and Plasticity in Atherosclerosis)

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21 pages, 1832 KB

Open AccessArticle

Nucleosome Clustering as a Biomarker and Mechanistic Switch for Reprogramming Cells

by Zhaoyuan Xu, Yinzhi Xu, Baiyan Li, Lidan You, Jing Liu and Hiroki Yokota

Cells 2026, 15(2), 113; https://doi.org/10.3390/cells15020113 - 8 Jan 2026

Abstract

Chromatin architecture is highly dynamic, undergoing nanoscale rearrangements throughout the cell cycle and in response to environmental cues. In this study, we employed high-resolution stochastic optical reconstruction microscopy (STORM) to visualize chromatin organization and cellular plasticity at the nanoscale in two osteosarcoma cell [...] Read more.

Chromatin architecture is highly dynamic, undergoing nanoscale rearrangements throughout the cell cycle and in response to environmental cues. In this study, we employed high-resolution stochastic optical reconstruction microscopy (STORM) to visualize chromatin organization and cellular plasticity at the nanoscale in two osteosarcoma cell lines, U2OS and MG63. To promote a tumor-suppressive bone microenvironment, we applied three biophysical modalities, namely mechanical vibration, electrical stimulation, and optical pulses, each previously linked to altered tumor behavior by reprogramming cells and generating induced tumor-suppressing (iTS) cells. These stimuli enlarged nuclear size and disrupted nuclear envelope integrity, as revealed by increased surface roughness. Critically, all three modalities transiently scattered nucleosome clusters, indicating chromatin decondensation as a hallmark of iTS cell generation. iTS cells exhibited elevated expression of histone demethylases lysine demethylase 3A (KDM3A) and lysine demethylase 4 (KDM4), accompanied by reduced levels of trimethylated histone H3 lysine 9 (H3K9me3). Consistently, pharmacological agents—Trichostatin A as a histone deacetylase inhibitor and chaetocin as a histone methyltransferase inhibitor—induced nucleosome scattering and converted U2OS cells into iTS cells, whose conditioned media exerted tumor-suppressive effects. Our findings highlight nucleosome clustering as a key epigenetic feature responsive to both biophysical and chemical cues, underscoring its role in microscale chromatin remodeling and reprogramming of the tumor microenvironment. Full article

(This article belongs to the Section Cellular Biophysics)

25 pages, 1230 KB

Open AccessReview

Targeting Cardiac Fibroblast Plasticity for Antifibrotic and Regenerative Therapy in Heart Failure

by Suchandrima Dutta, Sophie Chen, Waqas Ahmad, Wei Huang, Jialiang Liang and Yigang Wang

Cells 2026, 15(2), 112; https://doi.org/10.3390/cells15020112 (registering DOI) - 8 Jan 2026

Abstract

Cardiac fibrosis is a major component of heart failure (HF) and develops when reparative wound healing becomes chronic, leading to excessive extracellular matrix accumulation. Cardiac fibroblasts (CFs), the main regulators of matrix remodeling, are heterogeneous in developmental origins, regional localizations, and activation states. [...] Read more.

Cardiac fibrosis is a major component of heart failure (HF) and develops when reparative wound healing becomes chronic, leading to excessive extracellular matrix accumulation. Cardiac fibroblasts (CFs), the main regulators of matrix remodeling, are heterogeneous in developmental origins, regional localizations, and activation states. This diversity determines whether tissue repair resolves normally or progresses into maladaptive scarring that disrupts myocardial structure and function after injuries. Recent single-cell and spatial transcriptomic studies show that CFs exist in distinct yet interrelated molecular states in murine models and human cardiac tissue with specialized roles in matrix production, angiogenesis, immune signaling, and mechanical sensing. These insights redefine cardiac fibrosis as a dynamic and context-dependent process rather than a uniform cellular response. Although CFs are promising targets for preventing HF progression and enhancing cardiac remodeling, translation into effective therapies remains limited by the unclear heterogeneity of pathological fibroblasts, the lack of distinctive CF markers, and the broad activity of fibrogenic signaling pathways. In this review, we discuss the dynamics of CF activations during the development and progression of HF and assess the underlying pathways and mechanisms contributing to cardiac dysfunction. Additionally, we highlight the potential of targeting CFs for developing therapeutic strategies. These include nonspecific suppression of fibroblast activity and targeted modulation of the signaling pathways and cell populations that sustain chronic remodeling. Furthermore, we assess regenerative approaches that can reprogram fibroblasts or modulate their paracrine functions to restore functional myocardium. Integrating antifibrotic and regenerative strategies with advances in precision drug discovery and gene delivery offers a path toward reversing established fibrosis and achieving recovery in HF. Full article

(This article belongs to the Special Issue Signalling Mechanisms Regulating Cardiac Fibroblast Function)

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26 pages, 790 KB

Open AccessReview

Non-Apoptotic Programmed Cell Death: From Ultrastructural Characterization to Emerging Therapeutic Opportunities

by Philip Steiner, Lena Wiesbauer, Hubert H. Kerschbaum and Susanna Zierler

Cells 2026, 15(2), 111; https://doi.org/10.3390/cells15020111 - 8 Jan 2026

Abstract

Distinct forms of non-apoptotic programmed cell death (PCD) play a central role in human and animal health and their signaling cascades provide pharmacological targets for therapeutic interventions. Non-apoptotic modalities of programmed cell death include well characterized forms, such as ferroptosis, necroptosis, pyroptosis, autophagy, [...] Read more.

Distinct forms of non-apoptotic programmed cell death (PCD) play a central role in human and animal health and their signaling cascades provide pharmacological targets for therapeutic interventions. Non-apoptotic modalities of programmed cell death include well characterized forms, such as ferroptosis, necroptosis, pyroptosis, autophagy, paraptosis, as well as newly characterized varieties, such as cuproptosis, disulfidptosis, and erebosis. Each pathway exhibits unique molecular signaling signatures, ultrastructural characteristics, and functional outcomes that distinguish them from classical apoptosis. While pharmacological targets in the signaling cascade are promising objectives for overcoming apoptosis resistance in cancer therapy, inhibition of cell death in the myocardium or nervous system is critical for cytoprotection. This review provides detailed characterization and schematic visualization of cellular and subcellular hallmarks for each non-apoptotic PCD modality, facilitating their morphological identification. Understanding these diverse pathways is crucial for developing innovative therapeutic interventions in cancer, neurodegeneration, and inflammatory diseases. Full article

(This article belongs to the Special Issue Mechanisms and Therapies of Cell Death Pathways)

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