Cells

22 pages, 11282 KB

Open AccessArticle

Effects of N-Acetylcysteine and Alpha-Ketoglutarate on OVCAR3 Ovarian Cancer Cells: Insights from Integrative Bioinformatics and Experimental Validation

by Yasaman Khamineh, Sanaz Panahi-Alanagh, Samaneh Zolghadri, Laleh Mavaddatiyan, Ireneusz Ryszkiel, Agata Stanek and Mahmood Talkhabi

Cells 2026, 15(3), 281; https://doi.org/10.3390/cells15030281 (registering DOI) - 2 Feb 2026

Abstract

Ovarian cancer remains one of the leading causes of cancer-related mortality among women, underscoring the need for novel combination strategies that effectively inhibit tumor cell growth while limiting adverse effects. N-acetylcysteine (NAC) and alpha-ketoglutarate (AKG) are biologically active compounds with reported anticancer properties; [...] Read more.

Ovarian cancer remains one of the leading causes of cancer-related mortality among women, underscoring the need for novel combination strategies that effectively inhibit tumor cell growth while limiting adverse effects. N-acetylcysteine (NAC) and alpha-ketoglutarate (AKG) are biologically active compounds with reported anticancer properties; however, their combined effects in ovarian cancer are not well characterized. In this study, we applied an integrative approach combining network pharmacology analysis with in vitro experiments to investigate the effects of NAC and AKG on OVCAR3 ovarian cancer cells. Common molecular targets of NAC and AKG were identified by intersecting predicted compound targets with ovarian cancer-associated genes, followed by protein–protein interaction network construction and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Experimental validation assessed the effects of NAC and AKG, alone and in combination, on cell viability, apoptosis, migration, and clonogenic capacity. Network analysis identified 70 shared target genes enriched in pathways related to apoptosis, cellular stress responses, and cell migration. In vitro experiments demonstrated that combined treatment with NAC (10 mM) and AKG (100 µM) significantly reduced cell viability, increased apoptotic cell death, and markedly suppressed cell migration and colony formation compared with single-agent treatments. Overall, these findings indicate that the combination of NAC and AKG exerts enhanced inhibitory effects on ovarian cancer cell growth and motility in vitro. Full article

(This article belongs to the Special Issue Genomics and Cellular Mechanisms in Ovarian Cancer)

► Show Figures

Figure 1

12 pages, 427 KB

Open AccessArticle

Interleukin-38: A Candidate Biomarker for Disease Severity in Advanced Steatotic Liver Disease

by Valeria Wagner, Michael Mederer, Barbara Enrich, Veronika Cibulkova, Johanna Piater, Andreas Zollner, Rebecca Giquel-Fernandes, Herbert Tilg and Maria Effenberger

Cells 2026, 15(3), 280; https://doi.org/10.3390/cells15030280 (registering DOI) - 2 Feb 2026

Abstract

Background: Interleukin-38 (IL-38) is an anti-inflammatory IL-1—family cytokine implicated in limiting tissue injury by its anti-inflammatory character. We evaluated the diagnostic discrimination and prognostic relevance in steatotic liver disease (SLD). Methods: We conducted a prospective, monocentric cohort analysis of 184 patients with SLD [...] Read more.

Background: Interleukin-38 (IL-38) is an anti-inflammatory IL-1—family cytokine implicated in limiting tissue injury by its anti-inflammatory character. We evaluated the diagnostic discrimination and prognostic relevance in steatotic liver disease (SLD). Methods: We conducted a prospective, monocentric cohort analysis of 184 patients with SLD (n = 176) and healthy controls (n = 8). We tested group differences using Mann–Whitney U or Kruskal–Wallis; determined diagnostic quality using ROC curves. Logistic regression was used to assess the relationship with decompensation. Associations with MELD and routine laboratory parameters were modeled using Spearman correlation and linear regression. We analyzed survival using Kaplan–Meier and Cox regression. Findings: IL-38 concentrations were found to be higher in decompensated (n = 94) than in compensated patients (n = 82) (p < 0.001). MELD was positively associated with IL-38 (p < 0.001; 95% CI 0.057–0.120). This corresponds to a 9.2% increase in IL-38 per 1-point increase in MELD (95% CI 5.9–12.7%). IL-38 correlated positively with the MELD score (p < 0.001) and with bilirubin/AST/LDH. In the combination model (MELD + IL-38 ± CRP), a very good AUC ≈ 0.92 was achieved. Conclusion: IL-38 reflects the severity of steatotic liver disease and is therefore a potentially predictive biomarker for early risk stratification and therapy monitoring. Full article

► Show Figures

Figure 1

15 pages, 1969 KB

Open AccessArticle

Effect of the G-Protein-Coupled Receptor T2R14 on Proliferation and Cell Population Growth in Oral Cancer Cells

by Yongqiang Chen, Manikanta Kella, Kayla Austin, Rajinder P. Bhullar and Prashen Chelikani

Cells 2026, 15(3), 279; https://doi.org/10.3390/cells15030279 (registering DOI) - 1 Feb 2026

Abstract

Oral cancer is a leading cause of cancer-related deaths and significantly affects the quality of life of patients. However, many of its mechanisms remain unclear, and its treatment needs improvement. The G-protein-coupled receptor taste receptor type 2 member 14 (T2R14 or TAS2R14) is [...] Read more.

Oral cancer is a leading cause of cancer-related deaths and significantly affects the quality of life of patients. However, many of its mechanisms remain unclear, and its treatment needs improvement. The G-protein-coupled receptor taste receptor type 2 member 14 (T2R14 or TAS2R14) is expressed in various cancer types. However, few studies have investigated its roles in oral cancer, and its effects on oral cancer cell proliferation and growth are unknown. This study aimed to examine T2R14’s impact on proliferation and cell population growth (CPG) of oral cancer cells. TAS2R14 gene knockout was performed, and cell numbers, cell viability, and colony formation were measured. This study showed that TAS2R14 knockout in oral cancer cells significantly decreased calcium mobilization, increased cell numbers, colony formation, the proliferation marker proliferating cell nuclear antigen, and the phosphorylation of mechanistic target of rapamycin, but did not affect cell viability. These observations are consistent with the clinical data that higher TAS2R14 mRNA expression is associated with better survival of patients with oral cancer. Therefore, T2R14 downregulation increased oral cancer CPG, suggesting a tumor-suppressor-like role. The study’s findings could improve our understanding of T2R14 mechanisms and help develop strategies to advance oral cancer treatment by targeting T2R14. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors and Diseases)

► Show Figures

Figure 1

31 pages, 1115 KB

Open AccessReview

Peculiar Cat with Many Lives: PUMA in Viral Infections

by Zbigniew Wyżewski, Justyna Stępkowska, Pola Pruchniak, Adrianna Niedzielska, Karolina Paulina Gregorczyk-Zboroch and Matylda Barbara Mielcarska

Cells 2026, 15(3), 278; https://doi.org/10.3390/cells15030278 (registering DOI) - 1 Feb 2026

Abstract

Apoptosis is a natural mechanism that shapes morphogenesis and helps maintain tissue homeostasis in healthy organisms. It is also extensively studied in the context of pathologies such as cancer and viral infections. The course of the latter strictly depends on host cell viability; [...] Read more.

Apoptosis is a natural mechanism that shapes morphogenesis and helps maintain tissue homeostasis in healthy organisms. It is also extensively studied in the context of pathologies such as cancer and viral infections. The course of the latter strictly depends on host cell viability; therefore, regulators of apoptosis may play essential roles in distinct viral infections as well as virus-dependent diseases. The p53-upregulated modulator of apoptosis (PUMA), a pro-apoptotic member of the B-cell lymphoma 2 (Bcl-2) family, directly disrupts mitochondrial integrity, thereby promoting the intrinsic apoptotic pathway. PUMA-mediated cell death act as a double-edged sword that may either facilitate viral infection and its consequences or counteract them, depending on the infectious agent and the complex context of pathogen–host interactions. Accordingly, various viruses have evolved strategies to modulate host cell viability to their advantage by targeting PUMA—either by suppressing transcription of the PUMA gene, binding and inactivating the PUMA protein, or, conversely, inducing its production. In this work, we describe the role of PUMA in infections caused by distinct viruses and in associated diseases, viral strategies for modulating PUMA-related signaling pathways, and potential therapeutic implications. Full article

► Show Figures

Figure 1

21 pages, 3031 KB

Open AccessArticle

The Effects of BRCA1 and BRCA2 Promoter Methylation on Clinicopathological Characteristics and Clinical Outcomes in HGSOC

by Katarina Živić, Ivana Boljević, Milica Nedeljković, Milana Matović, Radmila Janković and Miljana Tanić

Cells 2026, 15(3), 277; https://doi.org/10.3390/cells15030277 (registering DOI) - 1 Feb 2026

Abstract

Ovarian cancer is a highly lethal disease. Tumors with a deficiency in the homologous recombination repair pathway (HRD) resulting from mutations in BRCA1/2 genes have a favorable response to platinum-based chemotherapy and targeted therapy with PARP inhibitors (PARPi) mediated by synthetic [...] Read more.

Ovarian cancer is a highly lethal disease. Tumors with a deficiency in the homologous recombination repair pathway (HRD) resulting from mutations in BRCA1/2 genes have a favorable response to platinum-based chemotherapy and targeted therapy with PARP inhibitors (PARPi) mediated by synthetic lethality. Promoter methylation of BRCA1/2 genes was previously associated with HRD, but little is known about whether it translates to clinical benefit. Here, we evaluated the prevalence of BRCA1/2 promoter methylation in HGSOC patients from Serbia and examined their clinicopathological characteristics and the effect on progression-free and overall survival. Using methylation-specific PCR, we screened for hypermethylation in the promoter region of BRCA1/2 genes in a cohort of 244 patients. We found fully methylated BRCA1 and BRCA2 promoter in 4.1% and 0.45% of patients, and 23.36% and 11.21% intermediately methylated cases, respectively. Full BRCA1/2 promoter methylation was significantly associated with younger age of onset (55 and 58 years, respectively) compared to BRCA1/2-mutated cases, suggestive of BRCAness phenotype. However, in the exploratory analysis of 68 patients with clinical follow-up, we did not find a strong survival advantage for BRCA1/2 methylated over BRCA1/2-intact cases, yet more moderate effects cannot be ruled out due to the cohort size. Full article

(This article belongs to the Special Issue Cellular and Molecular Insights into Gynecologic Tumors)

► Show Figures

Figure 1

22 pages, 4059 KB

Open AccessArticle

Mitochondria and Lipid Defects in Hereditary Progranulin-Related Frontotemporal Dementia

by Jon Ondaro, Jose Luis Zúñiga-Elizari, Mónica Zufiría, Maddi Garciandia-Arcelus, Ángela Sánchez Molleda, Miren Zulaica, Miguel Lafarga, Javier Riancho, Adolfo López de Munaín, Fermin Moreno, Francisco Javier Gil-Bea and Gorka Gerenu

Cells 2026, 15(3), 276; https://doi.org/10.3390/cells15030276 (registering DOI) - 1 Feb 2026

Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting individuals under 65 years of age, characterized by significant behavioral and language disabilities. Despite extensive research efforts, effective treatments for FTD remain elusive. Familial cases of FTD have been linked to genetic mutations in [...] Read more.

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting individuals under 65 years of age, characterized by significant behavioral and language disabilities. Despite extensive research efforts, effective treatments for FTD remain elusive. Familial cases of FTD have been linked to genetic mutations in several key genes, among these, mutations in granulin (GRN) account for 5–20% of cases, leading to haploinsufficiency of progranulin (PGRN), a multifunctional glycoprotein. This study investigates the cellular pathology associated with GRN insufficiency by using fibroblasts derived from FTD patients carrying the c.709-1G>A GRN mutation (FTD-GRN). These fibroblasts exhibited pathological hallmarks of FTD, including lysosomes, autophagosomes, and lipofuscin accumulation, mirroring observations in affected patient tissues. Notably, we report mitochondrial abnormalities, characterized by mitochondrial swelling which is associated with decreased mitochondrial respiration, and lipid droplet accumulation, reflecting altered lipid metabolism. Experimental supplementation with recombinant human progranulin (rhPGRN) was associated with recovery of lysosomal acidification and attenuation of mitochondrial and lipid abnormalities in vitro. This study reveals that GRN haploinsufficiency induces mitochondrial and lipid dysfunctions, suggesting that these pathways may contribute to FTD-GRN pathogenesis and could be of interest for therapeutic development. Full article

(This article belongs to the Section Cellular Neuroscience)

► Show Figures

Figure 1

11 pages, 748 KB

Open AccessReview

The Emerging Roles of GlycoRNAs in the Pathogenesis of Sepsis

by Xiang Li, Saichaitanya Nallajennugari, Joshua Fu, Anfal Faisal and Mingui Fu

Cells 2026, 15(3), 275; https://doi.org/10.3390/cells15030275 (registering DOI) - 1 Feb 2026

Abstract

Sepsis is a life-threatening condition caused by a dysregulated host immune response to infection, leading to systemic inflammation, organ dysfunction, and potentially death. Despite significant advances in understanding the pathophysiology of sepsis, effective therapeutic options remain limited, and mortality rates remain unacceptably high. [...] Read more.

Sepsis is a life-threatening condition caused by a dysregulated host immune response to infection, leading to systemic inflammation, organ dysfunction, and potentially death. Despite significant advances in understanding the pathophysiology of sepsis, effective therapeutic options remain limited, and mortality rates remain unacceptably high. Therefore, a deeper understanding of sepsis pathogenesis and the identification of novel therapeutic targets are urgently needed to improve patient outcomes. Recent studies have revealed that RNAs can undergo glycosylation, generating a previously unrecognized class of molecules known as glycosylated RNAs (glycoRNAs), which are localized on the outer surface of cells. GlycoRNAs are highly expressed in immune cells, and accumulating evidence indicates that they play important roles in regulating immune responses, including immune cell adhesion and infiltration, immune cell activation, and immune evasion. In addition, glycoRNAs are abundantly expressed on the epithelial cell surfaces of the respiratory, digestive, urinary, and reproductive systems, suggesting that glycoRNAs may function as a component of epithelial barriers that protect against pathogenic invasion. Collectively, these findings suggest that glycoRNAs may play a critical role in the pathogenesis of sepsis. This review summarizes the expression and functions of glycoRNAs in immune and barrier systems and highlights their potential roles during distinct immunological phases of sepsis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Sepsis: Pathogenesis, Immune Response, and Therapeutic Strategies)

► Show Figures

Figure 1

25 pages, 3301 KB

Open AccessArticle

Three-Dimensional Human Liver Micro Organoids and Bone Co-Culture Mimics Alcohol-Induced BMP Dysregulation and Bone Remodeling Defects

by Yuxuan Xin, Guanqiao Chen, Mohammad Majd Hammour, Xiang Gao, Fabian Springer, Elke Maurer, Andreas K. Nüssler and Romina H. Aspera-Werz

Cells 2026, 15(3), 274; https://doi.org/10.3390/cells15030274 (registering DOI) - 1 Feb 2026

Abstract

Hepatic osteodystrophy (HOD) is a frequent complication of chronic liver disease, marked by impaired osteogenesis and elevated fracture risk, particularly under sustained alcohol exposure. Bone morphogenetic proteins (BMPs), which play a crucial role in maintaining bone homeostasis, are dysregulated in alcoholic liver disease. [...] Read more.

Hepatic osteodystrophy (HOD) is a frequent complication of chronic liver disease, marked by impaired osteogenesis and elevated fracture risk, particularly under sustained alcohol exposure. Bone morphogenetic proteins (BMPs), which play a crucial role in maintaining bone homeostasis, are dysregulated in alcoholic liver disease. Specifically, decreased BMP2 and increased BMP13 have been linked to impaired osteogenesis and cartilage-like shifts in bone progenitors. A human in vitro system that recapitulates this hepatic BMP imbalance is needed to dissect mechanisms and identify targets. To address this, we established a long-term human three-dimensional liver–bone co-culture model that integrates hepatocytes (HepaRG), hepatic stellate cells (LX-2), and human umbilical vein endothelial cells (HUVECs) with bone scaffolds seeded with osteoblast precursors (SCP-1) and osteoclast precursors (THP-1). This study aimed to characterize the effects of chronic 50 mM alcohol exposure on hepatic fibrogenic activation and BMP ligand secretion, and to investigate the associated BMP-responsive signaling involved in bone cell lineage differentiation and functional activity. The results demonstrated alcohol-induced hepatic CYP2E1 activation and fibrogenic remodeling with EMT signatures, as well as a decrease in BMP2 and an increase in BMP13, without affecting BMP9. Liver-derived factors activated both canonical and non-canonical BMP signaling in bone progenitors, reduced osteoblast activity and mineralization, preserved osteoclast TRAP activity, and shifted the lineage toward chondrogenesis (SOX9↑, RUNX2↓). Notably, this BMP profile and skeletal phenotype reflect clinical observations in chronic liver disease, indicating that the model recapitulates key in vivo pathological features. This human liver micro-organoid co-culture reproduces alcohol-induced hepatic BMP dysregulation and downstream bone defects, offering an organoid-centric, microengineered platform for mechanistic studies and BMP-targeted therapeutic screening in HOD. Full article

(This article belongs to the Special Issue Recent Advances in Microfluidics and Organoids for Biomedical Applications)

► Show Figures

Figure 1

13 pages, 1759 KB

Open AccessArticle

The Highly Selective 5-HT_2B Receptor Antagonist MW073 Mitigates Aggressive Behavior in an Alzheimer’s Disease Mouse Model

by Erica Acquarone, Saktimayee M. Roy, Agnieszka Staniszewski, Daniel Martin Watterson and Ottavio Arancio

Cells 2026, 15(3), 273; https://doi.org/10.3390/cells15030273 (registering DOI) - 1 Feb 2026

Abstract

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia worldwide. Progressive synaptic dysfunction underlies declines in cognition, daily functioning, and the development of neuropsychiatric syndromes. Neuropsychiatric syndromes that include agitation and aggression affect 40–60% of patients and [...] Read more.

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia worldwide. Progressive synaptic dysfunction underlies declines in cognition, daily functioning, and the development of neuropsychiatric syndromes. Neuropsychiatric syndromes that include agitation and aggression affect 40–60% of patients and represent a major source of caregiver burden. Serotonin 5-HT_2B receptor levels are increased in the AD patient brain, and thus, treatment of AD animal models with the selective 5-HT_2B receptor antagonist MW073 in prevention or disease stage paradigms attenuates Aβ- or tau-induced dysfunction. Methods: We investigated the effects of MW073 treatment on the aggressive behavior of Tg2576 mice in a resident–intruder assay. Results: MW073 treatment significantly reduced aggressive behavior in male Tg2576 mice. Conclusions: MW073 efficacy in treating aggression in Tg2576 mice implicates 5-HT_2B receptor-mediated signaling in AD neuropsychiatric symptoms as well as cognitive and behavioral dysfunction. Full article

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

► Show Figures

Figure 1

20 pages, 3919 KB

Open AccessArticle

Dendrimer-Conjugated Glutamine Antagonist, D-TTM020, Ameliorates Brain Immune Dysregulation and Improves Neurobehavioral Deficits in the Mecp2-Deficient Mouse Model

by Preeti Vyas, Elizabeth Smith Khoury, Nirnath Sah, Anjali Sharma, Javier Allende Labastida, Elizabeth L. Wilkinson, Kathleen Lac, Nerketa N. L. Damiba, Amanda Fowler, Jinhuan Liu, Ashley Bedner, Pavel Majer, Tomás Tichý, Ajit G. Thomas, Rana Rais, Barbara S. Slusher, Rangaramanujam M. Kannan and Sujatha Kannan

Cells 2026, 15(3), 272; https://doi.org/10.3390/cells15030272 (registering DOI) - 1 Feb 2026

Abstract

Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by mutations in the MeCP2 gene, predominantly affecting females. Recent work with MeCP2-deficient mouse models showed a significant role in glutamatergic transmission, specifically microglia-produced glutamate and glutaminase upregulation, in RTT pathology. The glutamine antagonist 6-diazo-5-oxo-L-norleucine [...] Read more.

Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by mutations in the MeCP2 gene, predominantly affecting females. Recent work with MeCP2-deficient mouse models showed a significant role in glutamatergic transmission, specifically microglia-produced glutamate and glutaminase upregulation, in RTT pathology. The glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) is a potent glutaminase inhibitor; however, its use is limited due to systemic toxicities arising from its non-specific inhibition of glutamine-utilizing reactions. In this work, we determined whether dendrimer conjugation of a DON analog, TTM020 (or D-TTM020), results in targeted microglial glutaminase inhibition and behavioral changes in Mecp2 KO and heterozygous mice upon systemic administration. D-TTM020 at 1 mg/kg (drug basis) selectively and significantly inhibits glutaminase enzyme activity in the microglia of Mecp2 KO mice. Biweekly systemic treatment with 1 mg/kg of D-TTM020 improved the neurobehavioral phenotype in symptomatic Mecp2 KO and het mice. D-TTM020 also restored long-term retrieval of conditioned fear memory and improved cue responses during fear extinction after 8 weeks of treatment in symptomatic Mecp2 het mice. Our data indicate that selectively targeting glutamine metabolism in dysregulated glia using dendrimers represents a promising strategy that may offer a therapeutic approach for addressing glutamate dysregulation in RTT. Full article

(This article belongs to the Section Cellular Neuroscience)

► Show Figures

Figure 1

22 pages, 1507 KB

Open AccessReview

Stress-Driven Selective Neuronal Vulnerability in Charcot–Marie–Tooth Disease: From Prodromal Pathology to Therapeutic Implications

by Xianchao Pan, Jiming Xie, Zhiyu Li, Yuemeng Xiang, Yongzhen Yu, Qianqian Cai, Haidong Xu, Ying Wan and Juan Xing

Cells 2026, 15(3), 271; https://doi.org/10.3390/cells15030271 (registering DOI) - 31 Jan 2026

Abstract

Charcot–Marie–Tooth (CMT) disease represents the most prevalent inherited peripheral neuropathy with a broad range of clinical manifestations, inheritance patterns, and causative genes. The primary pathological hallmark is progressive degeneration, predominantly affecting sensory and motor neurons, leading to prominent sensory deficits and progressive motor [...] Read more.

Charcot–Marie–Tooth (CMT) disease represents the most prevalent inherited peripheral neuropathy with a broad range of clinical manifestations, inheritance patterns, and causative genes. The primary pathological hallmark is progressive degeneration, predominantly affecting sensory and motor neurons, leading to prominent sensory deficits and progressive motor impairments. While neuropathy-causing mutations in the ubiquitously expressed small heat shock protein HSPB1 account for a subset of axonal CMT cases, the mechanisms underlying the selective vulnerability of peripheral neurons remain poorly understood. In this review, we synthesize emerging evidence to reframe HSPB1-related CMT as a prototypical gene–environment interaction disorder. The unique anatomical exposure and high metabolic demands of the peripheral nervous system (PNS) render it particularly vulnerable to HSPB1 mutation-mediated homeostatic collapse, which manifests through three interconnected pathological axes: proteostatic disturbance, cytoskeletal dysregulation, and mitochondrial dysfunction. Crucially, these deficits converge to impair the stress adaptability of peripheral neurons, creating a maladaptive feedback loop wherein environmental stressors exacerbate intrinsic vulnerabilities. We further propose a phase-specific therapeutic framework that prioritizes early intervention during the clinically silent yet biologically active prodromal stage, when targeted modulation of the HSPB1 chaperone interactome and remodeling neural homeostasis may forestall neurodegeneration. This therapeutic paradigm shift from symptomatic management to preclinical neuroprotection underscores the imperative for precision medicine approaches in future CMT intervention. Full article

(This article belongs to the Special Issue Mechanisms, Biomarkers, and Therapeutics of Neurodegeneration)

21 pages, 2340 KB

Open AccessArticle

WWOX Induction Promotes Bcl-X_L and Mcl-1 Degradation Through a Lysosomal Pathway upon Stress Responses

by Yu-Han Su, Wei Chiang, Yi-Yu Wang, Yi-Hsi Kung, Pai-Shan Cheng, Tsung-Hao Chang, Nan-Shan Chang, Feng-Jie Lai and Li-Jin Hsu

Cells 2026, 15(3), 270; https://doi.org/10.3390/cells15030270 (registering DOI) - 31 Jan 2026

Abstract

The human WWOX gene resides on a common fragile site and is frequently deleted or altered during DNA replication. WWOX mutations are associated with various human diseases, including cancer, neurodegeneration, and developmental deficits. However, the regulation of WWOX expression remains largely unclear. We [...] Read more.

The human WWOX gene resides on a common fragile site and is frequently deleted or altered during DNA replication. WWOX mutations are associated with various human diseases, including cancer, neurodegeneration, and developmental deficits. However, the regulation of WWOX expression remains largely unclear. We demonstrated that stress responses, including serum deprivation, oxidative stress, and anticancer drug treatment, increase WWOX expression in human SCC-15 cells and wild-type mouse embryonic fibroblasts (MEFs) through transcriptional activation. Serum deprivation induces higher levels of reactive oxygen species and cell death in Wwox^+/+ than Wwox^−/− MEFs. Anti-apoptotic Bcl-2 family proteins regulate mitochondrial homeostasis and prevent serum deprivation-induced oxidative stress and cell death. Our results showed that serum starvation decreases protein expression levels of Bcl-X_L and Mcl-1 in Wwox^+/+ but not in Wwox^−/− MEFs. Serum starvation also fails to downregulate Bcl-X_L and Mcl-1 protein expression in WWOX-knockdown SCC-15 cells. Replenishment of ectopic WWOX induces downregulation of Bcl-X_L and Mcl-1 protein levels in Wwox^−/− MEFs after serum starvation. We determined that WWOX-mediated downregulation of Bcl-XL and Mcl-1 is accomplished through a lysosome-dependent protein degradation pathway. Moreover, a decline in reactive oxygen species generation by pretreatment of Wwox^+/+ MEFs with an antioxidant N-acetyl-L-cysteine leads to decreased WWOX induction upon serum starvation. Taken together, our results suggest that stress stimuli trigger WWOX induction by elevating the production of reactive oxygen species in cells, which promotes the degradation of Bcl-XL and Mcl-1 proteins via a lysosome-mediated pathway, thereby further aggravating oxidative stress and cell death. Full article

(This article belongs to the Special Issue The Role of Cell Signaling Pathway Starvation Therapy for Cancer)

19 pages, 1029 KB

Open AccessReview

Functional Changes in the Fallopian Tube: Environmental Factors, Lifestyle, Pathological Conditions and Pharmacological Agents

by Opalina Roy, Sandhya Kumari, Satish Kumar Adiga, Manjunath B. Joshi, Anujith Kumar, Ganesh Venkatraman, Nagarajan Kannan and Guruprasad Kalthur

Cells 2026, 15(3), 269; https://doi.org/10.3390/cells15030269 (registering DOI) - 31 Jan 2026

Abstract

The fallopian tubes are critical segments of the female reproductive tract and are essential for transporting gametes and embryos. It creates a conducive environment necessary for successful fertilization, early embryo development, and embryo transport. The cellular composition and function of the fallopian tube [...] Read more.

The fallopian tubes are critical segments of the female reproductive tract and are essential for transporting gametes and embryos. It creates a conducive environment necessary for successful fertilization, early embryo development, and embryo transport. The cellular composition and function of the fallopian tube are tightly regulated by the sex hormones estradiol and progesterone. Therefore, any pathological/ metabolic condition or exposure to exogenous agents with the potential to alter endocrine levels can have a significant impact on fallopian tube function and health. This review summarizes the effects of medications, infections, pathological conditions, lifestyle choices, and environmental factors that can significantly impact the morphology, histology, cellularity, and functionality of the fallopian tube. Full article

► Show Figures

Graphical abstract

16 pages, 1001 KB

Open AccessReview

Genomic Imprinting, Epigenetic Dysregulation, and Neuropsychiatric Mechanisms in Prader–Willi Syndrome: A Multi-Level Integrative Review

by Zofia Śledzikowska, Xawery Eryk Żukow, Zuzanna Małgorzata Antos and Napoleon Waszkiewicz

Cells 2026, 15(3), 268; https://doi.org/10.3390/cells15030268 (registering DOI) - 31 Jan 2026

Abstract

Prader–Willi syndrome (PWS) is a rare imprinting-related neurodevelopmental disorder caused by loss of paternally expressed genes within the chromosome 15q11–q13 region, including SNORD116, MAGEL2, and NDN. It provides a natural model for examining how genomic imprinting disruptions shape neural development and psychiatric vulnerability. [...] Read more.

Prader–Willi syndrome (PWS) is a rare imprinting-related neurodevelopmental disorder caused by loss of paternally expressed genes within the chromosome 15q11–q13 region, including SNORD116, MAGEL2, and NDN. It provides a natural model for examining how genomic imprinting disruptions shape neural development and psychiatric vulnerability. This review synthesizes current evidence to clarify the mechanistic pathways linking imprinting defects and epigenetic dysregulation to neuropsychiatric outcomes in PWS. Published studies—including patient-derived induced pluripotent stem cell (iPSC) models, animal knockout systems (e.g., Magel2-null models), transcriptomic and DNA methylation datasets, and human neuroimaging research—were identified through targeted searches of PubMed and Web of Science and integrated narratively rather than through systematic procedures. Across these data sources, deletion-type PWS is primarily associated with impaired neuronal maturation, altered serotonergic signaling, and locus-specific transcriptional dysregulation. Maternal uniparental disomy (mUPD) is characterized by broader epigenetic alterations within the imprinted domain, genome-wide transcriptional effects, dopaminergic pathway alterations, and disrupted prefrontal–limbic connectivity linked to increased psychosis risk. Importantly, available evidence supports substantial phenotypic and mechanistic overlap between PWS subtypes, with genotype–phenotype associations reflecting probabilistic tendencies rather than categorical distinctions. Collectively, convergent findings across molecular, neurochemical, and systems-level studies support a mechanistic continuum extending from imprinting defects to behavioral phenotypes. These insights position PWS as a translational model for understanding how epigenetic dysregulation contributes to psychiatric risk and highlight the need for genotype-informed, mechanistically grounded research to advance biomarker development and targeted therapeutic strategies. Full article

(This article belongs to the Section Cellular Neuroscience)

► Show Figures

Figure 1

23 pages, 5213 KB

Open AccessArticle

Identification and Experimental Validation of Triosephosphate Isomerase 1 as a Functional Biomarker of SHetA2 Sensitivity in Ovarian Cancer

by Laura F. Mortan, Zitha Redempta Isingizwe and Doris Mangiaracina Benbrook

Cells 2026, 15(3), 267; https://doi.org/10.3390/cells15030267 - 30 Jan 2026

Abstract

Background: Our objective was to identify and validate proteins that predict which patients with ovarian cancer will respond to SHetA2, an investigational drug in a phase 1 trial for patients with advanced or recurrent solid tumors (clinicaltrials.gov: NCT04928508). Methods: Cells were cultured from [...] Read more.

Background: Our objective was to identify and validate proteins that predict which patients with ovarian cancer will respond to SHetA2, an investigational drug in a phase 1 trial for patients with advanced or recurrent solid tumors (clinicaltrials.gov: NCT04928508). Methods: Cells were cultured from ascites from nine consented patients under an institutional review board-approved protocol. SHetA2 or olaparib sensitivities were determined using metabolic viability assays in ascites-derived cultures or ovarian cancer cell lines. Expression of four SHetA2 target proteins and sixteen proteins previously identified in an ovarian cancer mouse model were measured using microcapillary electrophoresis. Triosephosphate isomerase 1 (TPI1) was modulated by siRNA or lentivirus vector-mediated overexpression. Metabolites were measured using mass spectrometry. Results: TPI1 was elevated in SHetA2-sensitive compared to SHetA2-resistant ascites-derived cultures (two-way ANOVA q-value = 0.0003). The majority of (5/9) cultures were olaparib-resistant and SHetA2-sensitive. TPI1 was higher in olaparib-resistant cultures (two-way ANOVA q-value = 0.0003). Reduction in or overexpression of TPI1 reduced or increased SHetA2 potency, respectively, in two ovarian cancer cell lines (t-tests; p < 0.05). SHetA2 reduced the metabolites in glycolysis downstream of TPI1, the tricarboxylic acid cycle and oxidative pentose phosphate pathway. Conclusions: TPI1 is a candidate functional biomarker of SHetA2 sensitivity in ovarian cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Research on Cancer Drug Targets and Drug Resistance)

► Show Figures

Figure 1

19 pages, 10145 KB

Open AccessArticle

CD80-Mediated T-Cell Suppression by Cancer Stem-like Cells in Head and Neck Squamous Cell Carcinoma

by Mian Xiao, Lin Qiu, Qian Gao, Ruifeng Li, Jing Wang, Yanrui Feng, Xuefen Li and Xiyuan Ge

Cells 2026, 15(3), 266; https://doi.org/10.3390/cells15030266 - 30 Jan 2026

Abstract

Neoadjuvant chemoimmunotherapy has emerged as a promising treatment strategy for head and neck squamous cell carcinoma (HNSCC). There is an urgent need to improve patient responses to this approach. In this study, we aim to elucidate the mechanisms underlying poor response to neoadjuvant [...] Read more.

Neoadjuvant chemoimmunotherapy has emerged as a promising treatment strategy for head and neck squamous cell carcinoma (HNSCC). There is an urgent need to improve patient responses to this approach. In this study, we aim to elucidate the mechanisms underlying poor response to neoadjuvant chemoimmunotherapy and to identify strategies to enhance therapeutic efficacy in HNSCC. We identified a cancer stem-like cell (CSC) population enriched in patients with partial response (PR) to neoadjuvant chemoimmunotherapy, characterized by high CD80 expression. CD80 was likewise highly expressed in ALDH^highCD44⁺ and BMI1⁺ populations. Functionally, CD80 knockdown attenuated tumor-sphere-forming capacity and reduced the migration and invasion of tumor cells, whereas CD80 overexpression potentiated these pro-tumorigenic activities. Moreover, CD80 inhibition activated signaling pathways of Th1 immune responses and IL-2 production. CD80 blockade enhanced T cell cytotoxicity. In preclinical HNSCC models, inhibition of CD80 significantly decreased tumor burden, accumulated CD8⁺ T cells, and increased the production of cytotoxic effector molecules. Our data demonstrated that CD80 modulated tumor-cell stemness and malignant phenotype while restraining antitumor T cell immunity. Targeting CD80 augments antitumor immunity and provides a compelling strategy to enhance treatment responses to neoadjuvant chemoimmunotherapy in HNSCC. Full article

► Show Figures

Figure 1

33 pages, 1846 KB

Open AccessReview

Molecular and Cellular Mechanisms of Myocardial Ischemia and Reperfusion Injury: A Narrative Review

by Stefan Juricic, Jovana Klac, Sinisa Stojkovic, Branko Beleslin, Milorad Tesic, Ivana Jovanovic, Marko Banovic, Olga Petrovic, Srdjan Aleksandric, Natalija Vasic, Filip Simeunovic, Dejan Lazovic, Milica Stoiljkovic, Sashko Nikolov and Dejan Simeunovic

Cells 2026, 15(3), 265; https://doi.org/10.3390/cells15030265 - 30 Jan 2026

Abstract

Myocardial ischemia represents a state of reduced coronary perfusion with oxygenated blood, insufficient to meet the metabolic demands of the myocardium. Both acute and chronic ischemia trigger a cascade of cellular events that lead to disturbances in ionic balance, mitochondrial function and energy [...] Read more.

Myocardial ischemia represents a state of reduced coronary perfusion with oxygenated blood, insufficient to meet the metabolic demands of the myocardium. Both acute and chronic ischemia trigger a cascade of cellular events that lead to disturbances in ionic balance, mitochondrial function and energy metabolism. During ischemia, cardiomyocytes (CMs) shift from aerobic to anaerobic metabolism, resulting in adenosine triphosphate (ATP) depletion, loss of ionic homeostasis and calcium (Ca²⁺) overload that activate proteases, phospholipases and membrane damage. Reperfusion restores oxygen supply and prevents irreversible necrosis but paradoxically initiates additional injury in marginally viable myocardium. The reoxygenation phase induces excessive production of reactive oxygen species (ROS), endothelial dysfunction and a strong inflammatory response mediated by neutrophils, platelets and cytokines. Mitochondrial dysfunction and opening of the mitochondrial permeability transition pore (mPTP) further amplify oxidative stress and inflammation and trigger apoptosis and necroptosis. Understanding these intertwined cellular and molecular mechanisms remains essential for identifying novel therapeutic targets aimed at reducing reperfusion injury and improving myocardial recovery after ischemic events. Full article

► Show Figures

Figure 1

15 pages, 5280 KB

Open AccessArticle

Adipose Tissue-Derived Exosome and miR-142a-3p Alleviate Acute Lung Injury by Inhibiting HMGB1-Driven Autophagy

by Qianlin Long, Kejie Chen, Yizhu Li, Ruinan Peng, Yijian Yan, Jintao Ma, Jia Wang, Qiuyu Song, Yu Xue and Fengyuan Wang

Cells 2026, 15(3), 264; https://doi.org/10.3390/cells15030264 - 30 Jan 2026

Abstract

Acute lung injury (ALI) is a clinically severe respiratory disorder, of which autophagy is the crucial mechanism. Exosomes have the potential to treat ALI, but the role of adipose-derived exosomes (ADEs) in the autophagy of ALI remains unclear. Using an LPS-induced ALI model, [...] Read more.

Acute lung injury (ALI) is a clinically severe respiratory disorder, of which autophagy is the crucial mechanism. Exosomes have the potential to treat ALI, but the role of adipose-derived exosomes (ADEs) in the autophagy of ALI remains unclear. Using an LPS-induced ALI model, the effects of ADE isolated from a lean or diet-induced-obese (DIO) mouse and ADE-carried miRNAs were investigated. After administration of ADEs, the levels of autophagy-related molecules were determined by qRT-PCR, Western blotting, and immunohistochemical staining. Then, a miRNA targeting HMGB1 was screened by bioinformatic analysis and a dual-luciferase reporter assay, and its effect on the HMGB1-driven autophagy in an ALI mouse was investigated as ADEs. The data showed that LPS caused lung injury and activated HMGB1-driven autophagy. The ADEs from a lean mouse or DIO mouse significantly alleviated histopathological lesions, and they inhibited HMGB1-driven autophagy by down-regulating LC3, Beclin-1, and Atg5; the effects of ADEs were not significantly different between a lean and DIO mouse. Of the miRNAs carried by ADE, moreover, miR-142a-3p could specifically bind to HMGB1 mRNA, and up-regulation of pulmonary miR-142a-3p suppressed HMGB1-driven autophagy and relieved lung injuries. Our results indicated that miR-142a-3p and ADEs mitigate LPS-induced ALI by inhibiting HMGB1-driven autophagy, providing new insights on the prevention and treatment of ALI. Full article

► Show Figures

Figure 1

16 pages, 4900 KB

Open AccessArticle

Chitinase-like Proteins YKL-40 and YKL-39 in Colorectal Cancer

by Tsvetomira Ivanova, Maria Kazakova, Dorian Dikov, Angel M. Dzhambov, Nikolay Belev, Boyko Atanasov and Victoria Sarafian

Cells 2026, 15(3), 263; https://doi.org/10.3390/cells15030263 - 30 Jan 2026

Abstract

YKL-40 and YKL-39 chitinase-like proteins (CLPs) are secreted glycoproteins involved in inflammation, macrophage polarization, and carcinogenesis. Their expression is significantly upregulated in various inflammatory and immunological conditions, including several cancers, suggesting a role as potential diagnostic markers. Colorectal cancer (CRC) remains a significant [...] Read more.

YKL-40 and YKL-39 chitinase-like proteins (CLPs) are secreted glycoproteins involved in inflammation, macrophage polarization, and carcinogenesis. Their expression is significantly upregulated in various inflammatory and immunological conditions, including several cancers, suggesting a role as potential diagnostic markers. Colorectal cancer (CRC) remains a significant global health concern, with a continued need for reliable biomarkers to stratify patients and predict therapy response. In this study, we assessed tissue, plasma, and transcript levels of both CLPs in CRC. We found a strong association between their tissue expression and tumor budding. Notably, plasma YKL-39 levels were lower in CRC patients than in controls, while YKL-40 concentrations were higher in the patient group. Gene expression analysis for both CLPs in white blood cells (WBCs) did not reveal statistical significance between CRC patients and controls. These findings enhance our understanding of the clinical relevance of these molecular signatures and support their potential application as biomarkers in CRC stratification. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Tumor Pathogenesis)

► Show Figures

Figure 1

Journal Description

Cells

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI