Cells

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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52 pages, 4367 KB

Open AccessReview

The Microbiome–Neurodegeneration Interface: Mechanisms, Evidence, and Future Directions

by Lilia Böckels, Daniel Alexa, Dorin Cristian Antal, Cristina Gațcan, Cosmin Alecu, Kristina Kacani, Raul Andrei Crețu, Emanuel Andrei Piseru, Robert Valentin Bîlcu and Dan Iulian Cuciureanu

Cells 2026, 15(2), 135; https://doi.org/10.3390/cells15020135 - 12 Jan 2026

Abstract

The gut microbiota has emerged as a central regulator of the gut–brain axis, profoundly influencing neural, immune, and metabolic homeostasis. Increasing evidence indicates that disturbances in microbial composition and function contribute to the onset and progression of neurodegenerative diseases (NDs) through mechanisms involving [...] Read more.

The gut microbiota has emerged as a central regulator of the gut–brain axis, profoundly influencing neural, immune, and metabolic homeostasis. Increasing evidence indicates that disturbances in microbial composition and function contribute to the onset and progression of neurodegenerative diseases (NDs) through mechanisms involving neuroinflammation, oxidative stress, and impaired neurotransmission. Gut dysbiosis is characterized by a loss of microbial diversity, a reduction in beneficial commensals, and an enrichment of pro-inflammatory taxa. These shifts alter intestinal permeability and systemic immune tone, allowing microbial metabolites and immune mediators to affect central nervous system (CNS) integrity. Metabolites such as short-chain fatty acids (SCFAs), tryptophan derivatives, lipopolysaccharides (LPS), and trimethylamine N-oxide (TMAO) modulate blood–brain barrier (BBB) function, microglial activation, and neurotransmitter synthesis, linking intestinal imbalance to neuronal dysfunction and cognitive decline. Disruption of this gut–brain communication network promotes chronic inflammation and metabolic dysregulation, key features of neurodegenerative pathology. SCFA-producing and tryptophan-metabolizing bacteria appear to exert neuroprotective effects by modulating immune responses, epigenetic regulation, and neuronal resilience. The aim of this work was to comprehensively explore the current evidence on the bidirectional communication between the gut microbiota and the CNS, with a focus on identifying the principal molecular, immune, and metabolic mechanisms supported by the strongest and most consistent data. By integrating findings from recent human studies, this review sought to clarify how microbial composition and function influence neurochemical balance, immune activation, and BBB integrity, ultimately contributing to the onset and progression of neurodegenerative processes. Collectively, these findings position the gut microbiota as a dynamic interface between the enteric and CNS, capable of influencing neurodegenerative processes through immune and metabolic signaling. Full article

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38 pages, 2595 KB

Open AccessReview

Gene Editing Therapies Targeting Lipid Metabolism for Cardiovascular Disease: Tools, Delivery Strategies, and Clinical Progress

by Zhuoying Ren, Jun Zhou, Dongshan Yang, Yanhong Guo, Jifeng Zhang, Jie Xu and Y Eugene Chen

Cells 2026, 15(2), 134; https://doi.org/10.3390/cells15020134 - 12 Jan 2026

Abstract

Gene editing technologies have revolutionized therapeutic development, offering potentially curative and preventative strategies for cardiovascular disease (CVD), which remains a leading global cause of morbidity and mortality. This review provides an introduction to the state-of-the-art gene editing tools—including ZFNs, TALENs, CRISPR/Cas9 systems, base [...] Read more.

Gene editing technologies have revolutionized therapeutic development, offering potentially curative and preventative strategies for cardiovascular disease (CVD), which remains a leading global cause of morbidity and mortality. This review provides an introduction to the state-of-the-art gene editing tools—including ZFNs, TALENs, CRISPR/Cas9 systems, base editors, and prime editors—and evaluates their application in lipid metabolic pathways central to CVD pathogenesis. Emphasis is placed on targets such as PCSK9, ANGPTL3, CETP, APOC3, ASGR1, LPA, and IDOL, supported by findings from human genetics, preclinical models, and recent first-in-human trials. Emerging delivery vehicles (AAVs, LNPs, lentivirus, virus-like particles) and their translational implications are discussed. The review highlights ongoing clinical trials employing liver-targeted in vivo editing modalities (LivGETx-CVD) and provides insights into challenges in delivery, off-target effects, genotoxicity, and immunogenicity. Collectively, this review captures the rapid progress of LivGETx-CVD from conceptual innovation to clinical application, and positions gene editing as a transformative, single-dose strategy with the potential to redefine prevention and long-term management of dyslipidemia and atherosclerotic cardiovascular disease. Full article

(This article belongs to the Special Issue CRISPR-Based Genome Editing in Translational Research—Third Edition)

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11 pages, 488 KB

Open AccessArticle

Identification of Short Amino Acid Sequences That Correlate with Cytoplasmic Retention of Human Proteins

by Jay C. Brown and Baomin Wang

Cells 2026, 15(2), 133; https://doi.org/10.3390/cells15020133 - 12 Jan 2026

Abstract

One group of human proteins found in the cytoplasm, but not in the nucleus, is characterized by the presence of short (6–9 aa), specific amino acid sequences thought to be involved in retaining proteins in the cytoplasm (cytoplasmic retention sequences). While strong evidence [...] Read more.

One group of human proteins found in the cytoplasm, but not in the nucleus, is characterized by the presence of short (6–9 aa), specific amino acid sequences thought to be involved in retaining proteins in the cytoplasm (cytoplasmic retention sequences). While strong evidence supports the ability of some peptides to act in this way, the number of such supported cases is small. We have taken the view that the situation would be improved by enhancing the methods available to identify cytoplasmic retention (CR) sequences. Here, we describe an appropriate bioinformatic method to identify CR peptides using information about their location at the ends of cytoplasmic proteins. The method was then used to link seven different human cytoplasmic proteins with sequences suggested to have cytoplasmic retention activity. Further bioinformatic analysis was carried out with isoforms of the cytoplasmic proteins identified. Amino acid sequence information showed that while the proposed CR amino acid sequences can be the same or distinct in different protein isoforms, they are always located at the same site in the protein. For instance, while the proposed retention sequence of CCDC57 isoform X18 is MLARLVSNS, in isoform 7 it is SEPALNEL, yet the two sequences are each located between amino acids 5 and 13 in the CCDC57 sequence. The results support the view that the protein isoform is involved in determining the location of the CR sequence in a protein, while the amino acid sequence itself affects other variables such as the sub-region of the cytoplasm the protein needs to occupy. Overall, the study yielded identification of 15 candidate CR peptides in which 10 of the 15 have unrelated amino acid sequences. Full article

(This article belongs to the Section Intracellular and Plasma Membranes)

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17 pages, 3195 KB

Open AccessArticle

Aberrant Cell Cycle Gene Expression in a Transgenic Mouse Model of Alzheimer’s Disease

by Marika Lanza, Michele Scuruchi, Alessandra Saitta, Rossella Basilotta, Federica Aliquò, Giovanna Casili, Emanuela Esposito, Agata Copani, Salvatore Oddo and Antonella Caccamo

Cells 2026, 15(2), 132; https://doi.org/10.3390/cells15020132 - 12 Jan 2026

Abstract

Alzheimer’s disease (AD) is increasingly recognized as a disorder that extends beyond amyloid-β (Aβ) and tau pathology. To this end, growing evidence suggests that aberrant neuronal cell cycle re-entry (CCR) may contribute to neurodegeneration. To investigate this mechanism, we profiled the expression of [...] Read more.

Alzheimer’s disease (AD) is increasingly recognized as a disorder that extends beyond amyloid-β (Aβ) and tau pathology. To this end, growing evidence suggests that aberrant neuronal cell cycle re-entry (CCR) may contribute to neurodegeneration. To investigate this mechanism, we profiled the expression of 84 cell cycle-related genes in the brains of aged APP/PS1 mice, a widely used transgenic model of AD, and compared them with age-matched non-transgenic littermates. Our analysis revealed 32 differentially expressed genes (DEGs), 8 of which exhibited significant changes (fold change > 2, p < 0.05). Several of these DEGs, including CDC7 and CCNC, displayed consistent dysregulation in human AD brains as assessed using the AMP-AD knowledge portal, supporting their translational relevance. Furthermore, integration with miRNA prediction analyses identified candidate post-transcriptional regulators of these DEGs, highlighting novel layers of regulation. Collectively, our results provide the first systematic overview of cell cycle gene dysregulation in aged APP/PS1 mice, establish cross-species concordance with human AD, and propose miRNA–gene interactions as potential contributors to neuronal vulnerability. These findings underscore the importance of cell cycle pathways in AD pathogenesis and point to new avenues for therapeutic exploration. Full article

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45 pages, 2580 KB

Open AccessReview

Thermogenesis in Adipose Tissue: Adrenergic and Non-Adrenergic Pathways

by Md Arafat Hossain, Ankita Poojari and Atefeh Rabiee

Cells 2026, 15(2), 131; https://doi.org/10.3390/cells15020131 - 12 Jan 2026

Abstract

Obesity has reached epidemic proportions, driven by energy imbalance and limited capacity for adaptive thermogenesis. Brown (BAT) and beige adipose tissues dissipate energy through non-shivering thermogenesis (NST), primarily via uncoupling protein-1 (UCP1), making them attractive targets for increasing energy expenditure (EE). The canonical [...] Read more.

Obesity has reached epidemic proportions, driven by energy imbalance and limited capacity for adaptive thermogenesis. Brown (BAT) and beige adipose tissues dissipate energy through non-shivering thermogenesis (NST), primarily via uncoupling protein-1 (UCP1), making them attractive targets for increasing energy expenditure (EE). The canonical β-adrenergic pathway robustly activates NST in rodents through β3 adrenoceptors; however, translational success in humans has been limited by low β3 expression, off-target cardiovascular effects, and the emerging dominance of β2-mediated signaling in human BAT. Consequently, attention has shifted to non-adrenergic and UCP1-independent mechanisms that offer greater tissue distribution and improved safety profiles. This review examines a broad spectrum of alternative receptors and pathways—including GPRs, TRP channels, TGR5, GLP-1R, thyroid hormone receptors, estrogen receptors, growth hormone, BMPs, sirtuins, PPARs, and interleukin signaling—as well as futile substrate cycles (Ca²⁺, creatine, and glycerol-3-phosphate) that sustain thermogenesis in beige adipocytes and skeletal muscle. Pharmacological agents (natural compounds, peptides, and small molecules) and non-pharmacological interventions (cold exposure, exercise, diet, and time shift) targeting these pathways are critically evaluated. We highlight the translational gaps between rodent and human studies, the promise of multimodal therapies combining low-dose adrenergic agents with non-adrenergic activators, and emerging strategies such as sarco/endoplasmic reticulum calcium ATPase protein (SERCA) modulators and tissue-specific delivery. Ultimately, integrating adrenergic and non-adrenergic approaches holds the greatest potential for safe, effective, and sustainable obesity management. Full article

(This article belongs to the Special Issue Targeting Thermogenesis in Metabolic Disorders: Novel Pharmacological and Lifestyle Interventions)

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24 pages, 1724 KB

Open AccessReview

Enhancing the Nucleoside Analog Response with Translational Therapeutic Approaches to Overcome Resistance

by Jenna Thibodeau, Kian Hershberger, Sai Samanvitha M. Ramakrishna, Yongwei Su, Lauren Timmer, Bryce Brophy, Katherine Zhang, Holly Edwards, Jeffrey W. Taub and Yubin Ge

Cells 2026, 15(2), 130; https://doi.org/10.3390/cells15020130 - 12 Jan 2026

Abstract

Nucleoside analogs remain central to the treatment of hematologic malignancies and solid tumors, yet resistance frequently occurs, contributing to relapse and disease-related mortality. Rather than arising from a single mechanism, effective nucleoside analog activity requires successful navigation of multiple biological barriers, including cellular [...] Read more.

Nucleoside analogs remain central to the treatment of hematologic malignancies and solid tumors, yet resistance frequently occurs, contributing to relapse and disease-related mortality. Rather than arising from a single mechanism, effective nucleoside analog activity requires successful navigation of multiple biological barriers, including cellular uptake, intracellular activation, nucleotide pool balance, genome surveillance, and mitochondrial stress responses. This review integrates recent advances describing how alterations at each of these levels contribute to resistance to nucleoside analog therapies. We further highlight emerging therapeutic strategies centered on small-molecule inhibitors that exploit these vulnerabilities to enhance the efficacy of nucleoside analogs. Together, this integrative perspective supports the need for development of small molecule inhibitors and design of combination approaches aimed at restoring apoptotic competence and improving the use of nucleoside analog-based therapies for the treatment of cancer. Full article

(This article belongs to the Special Issue Small Molecule Inhibitors: A New Era in Cancer Treatment)

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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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 (registering DOI) - 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

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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 - 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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