Experimental Cell Research[JOURNAL]
Sun
200 papers
DMBX1 facilitates tumor progression via triggering epithelial-mesenchymal transition and cancer cell stemness mediated by DMBX1/PAX2/SOX5 axis in prostate cancer cells.
Li Z, Chen K, Pan Z … +3 more , Zhong L, Luo Y, Quan C
Exp Cell Res · 2026 Aug · PMID 42229817 · Publisher ↗
Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with metastatic and castration-resistant disease posing significant therapeutic challenges largely driven by epithelial-mesenchymal transi...
Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with metastatic and castration-resistant disease posing significant therapeutic challenges largely driven by epithelial-mesenchymal transition (EMT) and cancer stemness (CSC). This study identifies the transcription factor DMBX1 as a potential upstream regulator of these aggressive phenotypes in vitro and in subcutaneous xenograft models. DMBX1 is significantly upregulated in PCa tissues and cell lines, and its high expression correlates with advanced disease stage and poor patient prognosis. Functional assays demonstrated that DMBX1 knockdown suppressed PCa cell proliferation, migration, invasion, and tumor growth in vivo, while its overexpression promoted these malignant behaviors. Mechanistically, RNA sequencing and subsequent analyses revealed that DMBX1 transcriptionally activates PAX2 by directly binding to its promoter. DMBX1 and PAX2 proteins physically interact and form a complex that co-occupies the promoter of the core pluripotency factor SOX5, synergistically driving its expression. This novel DMBX1/PAX2/SOX5 axis facilitates PCa progression by concurrently activating the PI3K/AKT, MAPK, and JAK/STAT3 signaling pathways, thereby altering the expression of EMT- and CSC-related markers. Collectively, our findings establish the DMBX1/PAX2/SOX5 transcriptional axis as a potential regulator associated with the control of EMT- and CSC-related markers in prostate cancer, revealing a crucial signaling hub and a promising therapeutic target for advanced PCa.
Nicotinamide N-methyltransferase in inflammatory bowel disease: Multidimensional regulation, mechanistic insights, and therapeutic potential.
Liu A, Zhu XJ, Sun WD … +3 more , Bi SZ, Zhang CY, Li JH
Exp Cell Res · 2026 Aug · PMID 42229816 · Publisher ↗
Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder involving immune, metabolic, microbial, and epigenetic dysregulation. Nicotinamide N-methyltransferase (NNMT) connects nicotinamide metabolis...
Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder involving immune, metabolic, microbial, and epigenetic dysregulation. Nicotinamide N-methyltransferase (NNMT) connects nicotinamide metabolism with NAD availability, methyl-donor homeostasis, and epigenetic regulation. Accumulating evidence shows that NNMT is upregulated in intestinal tissues from patients with IBD and may promote disease progression by reducing nicotinamide adenine dinucleotide (NAD) availability, increasing homocysteine (Hcy) accumulation, and disturbing DNA and histone methylation. These changes may contribute to mitochondrial dysfunction, epithelial barrier impairment, gut microbiota dysbiosis, and enteric nervous system disturbance. This review summarizes current evidence on the role of NNMT in IBD and discusses emerging NNMT-targeted strategies, including small-molecule inhibitors, RNA-based silencing approaches, and exercise-based interventions. Collectively, NNMT represents a metabolic-epigenetic hub in IBD pathogenesis and a promising target for future therapeutic development.
SLC16A9-mediated uric acid uptake promotes myocardial hypertrophy in dilated cardiomyopathy via NLRP3 inflammasome activation.
Hu Z, Ding Y, Wang T … +2 more , Hou X, Song Q
Exp Cell Res · 2026 Aug · PMID 42208843 · Publisher ↗
BACKGROUND: Dilated cardiomyopathy (DCM) is a leading cause of heart failure with limited therapeutic options. Elevated uric acid (UA) levels serve as an independent risk factor for cardiovascular diseases, yet the speci...
BACKGROUND: Dilated cardiomyopathy (DCM) is a leading cause of heart failure with limited therapeutic options. Elevated uric acid (UA) levels serve as an independent risk factor for cardiovascular diseases, yet the specific mechanisms mediating cardiomyocyte UA uptake remain elusive. This study aimed to identify novel targets that regulate myocardial UA transport and to elucidate their role in the progression of DCM. METHODS: Differentially expressed genes were identified from four GEO transcriptome datasets (GSE3586, GSE79962, GSE84796, and GSE120895). The functional role of solute carrier family 16 member 9 (SLC16A9) was validated in doxorubicin-induced DCM mice and in H9c2 cells treated with exogenous UA. SLC16A9 was silenced using shRNA in vitro and AAV9-mediated gene delivery in vivo. UA concentrations, NLRP3 inflammasome activation, and myocardial hypertrophy were assessed. Paracrine effects were evaluated using co-culture systems. RESULTS: SLC16A9 was identified as a consistently upregulated transporter across all four datasets. Myocardial SLC16A9 expression was positively correlated with tissue UA levels. SLC16A9 silencing attenuated intracellular UA accumulation without affecting xanthine oxidase activity in UA-treated cardiomyocytes. Mechanistically, UA uptake activated the NLRP3 inflammasome pathway, promoting cardiomyocyte hypertrophy and transforming growth factor β1 (TGF-β1)-mediated fibroblast activation via paracrine signaling. Therapeutic SLC16A9 silencing in vivo significantly reduced myocardial hypertrophy and interstitial fibrosis, with combined SLC16A9 silencing and allopurinol treatment providing additive benefits. CONCLUSION: SLC16A9 serves as a critical mediator of UA uptake in the DCM myocardium. Silencing SLC16A9 reduces intracellular UA accumulation, thereby suppressing the NLRP3-TGF-β1 signaling cascade and effectively alleviating myocardial hypertrophy. These findings provide a new molecular target for the precise treatment of DCM.
Circ_0000376 protects against post cardiac arrest brain injury by sponging mmu-let-7b-5p to preserve CCND1 and metabolic homeostasis.
Lin L, Zhao Y, Liu X … +4 more , Huang X, Huang X, Pan M, Lin J
Exp Cell Res · 2026 Aug · PMID 42203096 · Publisher ↗
BACKGROUND: Post cardiac arrest brain injury (PCABI) results from global ischemia-reperfusion. Circular RNAs (circRNAs) are stable regulators of post transcriptional networks that may modulate neuronal survival and metab...
BACKGROUND: Post cardiac arrest brain injury (PCABI) results from global ischemia-reperfusion. Circular RNAs (circRNAs) are stable regulators of post transcriptional networks that may modulate neuronal survival and metabolism after ischemic injury. We investigated the role and mechanism of mmu_circ_0000376 (circ_0000376) in PCABI. METHODS: Through integrated bioinformatics analysis of circular RNA/microRNA/messenger RNA datasets via the GEO platform, a regulatory network involving circ_0000376/mmu-let-7b-5p/CCND1 was identified. We validated its circular structure, stability, and cytoplasmic localization in HT22 neuronal cells. Through in vitro and in vivo experiments modulating circ_0000376 expression, we investigated cellular functions by assessing cell viability, apoptosis (Annexin V/PI staining, TUNEL, caspase/Bcl-2 family proteins), and mitochondrial/energy parameters (ATP, glucose consumption, lactate, G6PD activity). RESULTS: Circ_0000376 is a stable, cytoplasmic circRNA. Overexpression of Circ_0000376 reduced ischemia-reperfusion injury induced ROS, preserved ATP and glycolytic flux, increased G6PD activity, decreased apoptosis, and restored CCND1 and Bcl 2 while lowering Bax and cleaved caspases. Bioinformatic and reporter assays showed circ_0000376 sponges mmu-let-7b-5p, relieving repression of CCND1. mmu-let-7b-5p overexpression or CCND1 knockdown reversed circ_0000376 mediated protection. AAV mediated circ_0000376 overexpression in mice decreased hippocampal apoptosis and restored CCND1 in vivo. CONCLUSIONS: Circ_0000376/mmu-let-7b-5p/CCND1 axis mitigates neuronal apoptosis and metabolic dysfunction after ischemic injury. Targeting this ceRNA network may offer a novel neuroprotective strategy for PCABI.
Amyloid-β aggregation disrupts actomyosin architecture and impairs contractility in human brain vascular smooth muscle cells.
Kobayashi H, Moizumi A, Maeda T … +3 more , Kurita H, Tokuraku K, Kuragano M
Exp Cell Res · 2026 Aug · PMID 42203095 · Publisher ↗
Amyloid-β (Aβ) accumulation within cerebral vessels underlies cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). In CAA, Aβ deposits along leptomeningeal and cortical vessel walls are strongly associated wit...
Amyloid-β (Aβ) accumulation within cerebral vessels underlies cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). In CAA, Aβ deposits along leptomeningeal and cortical vessel walls are strongly associated with intracerebral hemorrhage and vascular dysfunction. However, the cellular mechanisms remain incompletely understood. Based on our prior work showing that aggregated Aβ disrupts human brain microvascular endothelial cells, we now address the mural layer by testing how Aβ affects human brain vascular smooth muscle cells (hBSMCs), focusing on actomyosin architecture and contractile function to comprehensively reveal the effects of Aβ on the cerebral vasculature. We combined single-cell imaging of quantum dot-labeled Aβ (QDAβ) with F-actin labeling (Alexa Fluor 488-phalloidin/SiR-actin), confocal 3D reconstructions, and a collagen gel contraction assay to associate Aβ deposition dynamics with cytoskeletal organization and force output. Aβ formed deposits at the cell edge of hBSMCs, accompanied by disorganization of the F-actin network and the emergence of abnormal F-actin aggregates. In addition, time-lapse imaging revealed the progressive accumulation of QDAβ-positive deposits with concomitant disorganization of stress fibers and the condensation of activated myosin II. Functionally, gels containing Aβ-exposed hBSMCs failed to shrink compared with non-treated/DMSO controls, consistent with reduced hBSMC-mediated matrix contraction. Together, these data suggest that Aβ deposition is associated with disorganization of cortical and contractile actin networks in hBSMCs and reduced hBSMC-mediated matrix contraction, providing a potential cellular framework linking local cytoskeletal pathology to impaired vasomotion and perivascular clearance in CAA.
CRISPR/Cas9-induced chemR23 knock-out improves arterial inflammation in atherosclerotic mice.
Lu Y, Zhong S, Chen L … +4 more , Li Z, Zhang M, Wang Y, Cao J
Exp Cell Res · 2026 Jul · PMID 42191086 · Publisher ↗
BACKGROUND AND PURPOSE: Emerging evidence implicates chemerin, a chemoattractant protein, in the pathogenesis of atherosclerosis (AS). Yet, the role of its receptor, Chemokine-Like Receptor 1 (ChemR23), in AS remains eni...
BACKGROUND AND PURPOSE: Emerging evidence implicates chemerin, a chemoattractant protein, in the pathogenesis of atherosclerosis (AS). Yet, the role of its receptor, Chemokine-Like Receptor 1 (ChemR23), in AS remains enigmatic. Leveraging CRISPR/Cas9 genome editing, this study delineates the impact of ChemR23 ablation in an AS murine model, aiming to unravel its mechanistic involvement in AS pathophysiology. METHODS: Employing CRISPR/Cas9, we orchestrated a targeted knockout of the ChemR23 gene in C57BL/6J wild-type (WT) mice, followed by an eight-month high-fat dietary regimen. High-fat diet-fed WT mice and their standard diet counterparts constituted the experimental and baseline cohorts, respectively. We deployed commercial assay kits to quantify lipid metabolism markers and inflammatory mediators. Histopathological changes in arterial plaques and lipid deposition were appraised using Hematoxylin & Eosin and Oil Red O staining. Western blotting, Immunohistochemistry, and Immunofluorescence staining were harnessed to interrogate plaque inflammatory signaling and autophagy-related protein expression. Macrophage polarization dynamics were dissected via flow cytometry, and foam cell gene expression profiles were ascertained through quantitative real-time PCR. RESULTS: ChemR23 knockout conferred ameliorative effects on lipid metabolic aberrations and plaque stability in AS mice, evidenced by diminished lipid accrual in plaques. It attenuated the activation of the NF-κB inflammatory cascade, fostered an M2 macrophage polarization bias, and impeded the macrophage-to-foam cell transition. Notably, ChemR23 ablation suppressed autophagic activities within the plaques. CONCLUSION: Targeted ChemR23 gene disruption in mice manifests as a modulator of inflammatory and autophagic pathways, thereby mitigating AS exacerbation. This positions ChemR23 as a promising molecular candidate for strategic AS therapeutics.
Zyxin deficiency aggravates podocyte injury in hypertensive nephropathy.
He FF, Chen YY, Wang YM … +6 more , Huang W, Du SJ, Song AN, Hao Y, Zhang XL, Zhang C
Exp Cell Res · 2026 Jul · PMID 42176770 · Publisher ↗
Podocyte injury and detachment are early cellular events in hypertensive nephropathy, yet their underlying mechanisms are not well clarified. Zyxin, a mechanotransducer located at focal adhesions, regulates actin cytoske...
Podocyte injury and detachment are early cellular events in hypertensive nephropathy, yet their underlying mechanisms are not well clarified. Zyxin, a mechanotransducer located at focal adhesions, regulates actin cytoskeleton remodeling and exhibits diverse biological functions. However, its role in podocytes is poorly understood. In this study, we constructed a hypertensive nephropathy model in podocyte-specific zyxin knockout mice to explore the role of zyxin in hypertensive conditions. In vitro, mechanical stretch and Angiotensin II (AngII) were used to stimulate podocytes. Western blot, real-time PCR, and immunofluorescence were performed to underscore underlying mechanisms. We identified decreased zyxin levels in the glomeruli of a hypertensive nephropathy mouse model. Mechanical stretch and AngII altered zyxin expression and distribution in podocytes. Moreover, podocyte-specific zyxin knockout worsened hypertension-induced renal dysfunction, glomerulosclerosis, glomerular basement membrane thickening, foot process effacement, and podocyte loss. Zyxin knockdown disrupted the actin cytoskeleton, accompanied by reduced α-actinin-4 expression and changes in focal adhesion proteins, including vinculin and paxillin, which may contribute to altered podocyte motility and adhesion. These findings indicate that zyxin is involved in the regulation of podocyte cytoskeletal organization and cell behavior, likely through coordinated effects on multiple cytoskeletal and focal adhesion-related pathways rather than a single downstream mediator. In this context, zyxin may play a protective role in maintaining podocyte stability during hypertensive nephropathy.
Indole-3-lactic acid attenuates hepatic stellate cell pyroptosis and liver fibrosis associated with NLRP3 signaling.
Shang F, Cui X, Wang B … +2 more , Liu F, Tian Q
Exp Cell Res · 2026 Aug · PMID 42167714 · Publisher ↗
BACKGROUND AND AIMS: Hepatic stellate cell (HSC) pyroptosis is increasingly recognized as an important contributor to liver inflammation and fibrosis; however, the role of endogenous metabolites in regulating this proces...
BACKGROUND AND AIMS: Hepatic stellate cell (HSC) pyroptosis is increasingly recognized as an important contributor to liver inflammation and fibrosis; however, the role of endogenous metabolites in regulating this process remains incompletely understood. This study aimed to investigate the potential function and mechanism of the tryptophan-derived metabolite indole-3-lactic acid (ILA) in HSC pyroptosis and liver fibrosis. METHODS: Serum ILA from cirrhosis patients was quantified by Gas Chromatography-Mass Spectrometry. In vitro, HSC pyroptosis induced by lipopolysaccharide (LPS) and nigericin was used to assess the effects of ILA, an aryl hydrocarbon receptor (AHR) antagonist, siRNA-mediated AHR knockdown, and NLRP3 overexpression. In vivo, a carbon tetrachloride (CCl)-induced liver fibrosis model was established, and mice were treated with ILA with or without adeno-associated virus-mediated hepatic NLRP3 overexpression. RESULTS: ILA levels were significantly reduced in patients with cirrhosis compared to controls. In vitro, ILA attenuated pyroptosis-associated changes in HSCs and was associated with activation of AHR signaling and modulation of the NLRP3 inflammasome pathway. These effects were diminished by AHR blockade or NLRP3 overexpression. In vivo, ILA was associated with improved liver histology and reduced markers of hepatic pyroptosis and inflammation, whereas NLRP3 overexpression partially attenuated these effects. CONCLUSION: ILA could suppress HSC pyroptosis and alleviate liver fibrosis, potentially through AHR-dependent inhibition of NLRP3. These findings provide insight into the role of tryptophan-derived metabolites in liver fibrosis and suggest that ILA may represent a potential therapeutic candidate.
Signal regulatory protein γ is associated with an exhaustion-prone immune microenvironment in metastatic melanoma.
Shao X, Li X, Gao J … +6 more , Wu S, Jia S, Sun R, Wang X, Dai X, Zhang Y
Exp Cell Res · 2026 Jul · PMID 42167713 · Publisher ↗
Identifying determinants of immune microenvironment remodeling in metastatic melanoma is critical for improving prognostic assessment and therapeutic stratification. In this study, we examined the expression and clinical...
Identifying determinants of immune microenvironment remodeling in metastatic melanoma is critical for improving prognostic assessment and therapeutic stratification. In this study, we examined the expression and clinical significance of signal regulatory protein γ (SIRPG) in skin cutaneous melanoma (SKCM) through a combination of database mining, single-cell transcriptomics, and immunohistochemical (IHC) validation. SIRPG was significantly elevated in SKCM tissues compared with normal skin, and higher expression levels were associated with prolonged overall and disease-free survival. Functional and pathway analyses revealed that SIRPG was intimately linked to immune-related processes, and correlative analyses demonstrated strong associations between SIRPG expression and both immune cell infiltration and checkpoint molecule expression, with these associations being more pronounced in metastases than in primary tumors. Single-cell RNA sequencing further localized SIRPG expression predominantly to CD8 exhausted T cells within metastatic lesions, and multiplex immunofluorescence confirmed enriched co-expression of SIRPG and programmed cell death protein 1 (PD-1) at the protein level. Taken together, these findings implicate SIRPG in the establishment of an exhaustion-prone immunosuppressive microenvironment in metastatic melanoma and highlight its potential utility as a biomarker for disease progression and immunotherapeutic response.
Cardiomyopathy phenotypes caused by a heterozygous MYBPC3 mutation revealed in different hiPSC cardiac models.
Yiangou L, Groen E, Erbì M … +6 more , Stein J, Blanch-Asensio A, Visser T, Mol MPH, Mummery CL, Davis RP
Exp Cell Res · 2026 Jul · PMID 42144094 · Publisher ↗
Hypertrophic cardiomyopathy (HCM) is a complex cardiac disorder caused by mutations in sarcomeric protein genes, showing variable penetrance and disease severity among patients. Key pathological features include left ven...
Hypertrophic cardiomyopathy (HCM) is a complex cardiac disorder caused by mutations in sarcomeric protein genes, showing variable penetrance and disease severity among patients. Key pathological features include left ventricular hypertrophy, myofibrillar disarray and contractile defects. Here, we used human induced pluripotent stem cells (hiPSCs) carrying the MYBPC3-c.2373insG mutation to investigate disease phenotypes across three in vitro platforms: cardiac microtissues (cMTs) generated from pre-differentiated cells, cardioids formed directly from hiPSCs and 2D hiPSC-derived cardiomyocytes. Both 3D models exhibited either altered contractile properties or calcium transients compared to isogenic controls, mirroring hypocontractility which is observed in some patients. In contrast, MYBPC3-c.2373insG hiPSC-derived cardiomyocytes cultured in 2D showed disrupted sarcomere organization and altered metabolism with increased oxygen consumption rate, but no measurable contractility defects. In addition, cMTs displayed a haploinsufficient phenotype, consistent with clinical observations in patients harbouring this mutation. Together, these findings show that different features of HCM pathology may best be revealed using different in vitro models, underscoring the need to select systems appropriate to the biological question. This work provides a platform to further explore the mechanisms underlying HCM, offering insights into how this condition might be more effectively studied and, eventually, treated.
Single-cell and spatial analyses identify a glycolysis-high state driven by STOML2 in epithelial ovarian cancer.
Liu L, Ren B, Zhu Y … +5 more , Yang X, Sun Y, Zhu D, Zhou Y, Ren Q
Exp Cell Res · 2026 Aug · PMID 42142700 · Publisher ↗
OBJECTIVE: Metabolic heterogeneity contributes to therapeutic resistance and poor prognosis in epithelial ovarian cancer (EOC), yet the regulatory drivers of aggressive glycolytic states remain incompletely defined. We a...
OBJECTIVE: Metabolic heterogeneity contributes to therapeutic resistance and poor prognosis in epithelial ovarian cancer (EOC), yet the regulatory drivers of aggressive glycolytic states remain incompletely defined. We aimed to delineate glycolysis-associated malignant epithelial states and identify actionable regulatory hubs. METHODS: We integrated single-cell RNA sequencing with spatial transcriptomics to map metabolic programmes in the ovarian cancer microenvironment. High-dimensional weighted gene co-expression network analysis (hdWGCNA) and differential expression analyses were used to nominate glycolysis-associated modules and hub candidates. A multi-cohort machine-learning framework was applied to construct and validate a prognostic signature using TCGA-OV and independent GEO cohorts. STOML2 was functionally validated in A2780 and SKOV3 cells using gain- and loss-of-function approaches, phenotypic assays, Seahorse extracellular flux analysis, and pharmacological modulation of AKT/mTOR signalling. RESULTS: Single-cell analyses identified a malignant epithelial subpopulation with high glycolytic activity (HGS) and spatial transcriptomics confirmed heterogeneous enrichment of glycolysis-high regions within tumour areas. HdWGCNA prioritised a glycolysis-linked module, from which STOML2 emerged as a central hub. A STOML2-containing prognostic signature robustly stratified risk across multiple cohorts. Experimentally, STOML2 promoted proliferation, clonogenicity, migration and invasion, suppressed apoptosis, and enhanced glycolytic output (increased glucose uptake, lactate production and ECAR) with reciprocal changes in respiratory activity. Mechanistically, STOML2 activated AKT and mTOR phosphorylation; AKT activation partially rescued the metabolic and growth defects induced by STOML2 knockdown, whereas AKT inhibition blunted STOML2-driven glycolysis and malignant phenotypes. CONCLUSION: STOML2 links a glycolysis-high malignant epithelial state to AKT/mTOR-dependent metabolic reprogramming and tumour aggressiveness in EOC. These findings support STOML2 as a prognostic biomarker and a potential therapeutic vulnerability in metabolically aggressive ovarian tumours.
Overexpression of SOX9 drives pulmonary fibrosis by regulating PKN2 to promote fibroblast-to-myofibroblast transformation.
Yuan Y, Geng J, Li JJ … +3 more , Zhou C, Chen JH, Jin R
Exp Cell Res · 2026 Jul · PMID 42142699 · Publisher ↗
Pulmonary fibrosis is a group of interstitial lung diseases caused by various aetiologies, leading to the destruction of tissue architecture and loss of physiological function. In recent years, the incidence of pulmonary...
Pulmonary fibrosis is a group of interstitial lung diseases caused by various aetiologies, leading to the destruction of tissue architecture and loss of physiological function. In recent years, the incidence of pulmonary fibrosis has been rising annually, and the fibroblast-to-myofibroblast transition (FMT) in human pulmonary fibroblasts is considered a key factor in the pathogenesis of pulmonary fibrosis. Protein kinase N2 (PKN2), as a member of the protein kinase N family, has been reported in the literature to be directly associated with pulmonary fibrosis; however, the pathways through which it participates in the progression of pulmonary fibrosis remain unclear. This study aims to investigate the biological functions of PKN2 in pulmonary fibrosis and the regulatory mechanisms of its upstream molecules. The findings reveal that PKN2 expression is significantly upregulated in human pulmonary fibroblasts following treatment with transforming growth factor-β1 (TGF-β1). Overexpression of PKN2 promotes the upregulation of stromal cell markers following TGF-β1 treatment, thereby facilitating the FMT process. In TGF-β1-induced MRC-5 cells, PKN2 also enhances proliferation and migration capacity. Furthermore, the transcription factor sex-determining region Y-box protein 9 (SOX9) was found to bind to the PKN2 promoter region and promote its expression levels. These results indicate that the SOX9/PKN2 transcriptional axis plays a role in promoting FMT in TGF-β1-induced MRC-5 cells, whilst enhancing cell proliferation and migration capacity; this suggests that targeting PKN2 holds promise for the development of therapeutic approaches for pulmonary fibrosis.
A novel chalcone analog inhibits cancer stemness in CD44 and CD133 populations via suppression of ERK signaling.
Baek S, Jang S, Lee SY … +10 more , Choi SL, Yang JY, Park JH, Kim BS, Kim SH, Lee JJ, Lee SH, Moon BS, Yoon CW, Lee KP
Exp Cell Res · 2026 Jul · PMID 42142698 · Publisher ↗
Cancer stem-like cells (CSC) that express cluster of differentiation (CD)44 or CD133 contribute to tumor aggressiveness, therapeutic resistance, and disease recurrence across multiple malignancies. Consequently, current...
Cancer stem-like cells (CSC) that express cluster of differentiation (CD)44 or CD133 contribute to tumor aggressiveness, therapeutic resistance, and disease recurrence across multiple malignancies. Consequently, current therapeutic modalities frequently fail to achieve durable disease control; hence, novel therapeutic strategies are urgently required. Therapeutic strategies that disrupt CSC maintenance may therefore contribute to more durable cancer control. Suitably, chalcone-based analogs have emerged as promising anticancer candidates. Therefore, this study aimed to investigate the effects of a novel chalcone analog 1 (UR-1) on CSC populations characterized by CD44 or CD133 phenotypes using complementary three-dimensional culture systems and in vivo models. CD44 or CD133 CSC populations were enriched from human head and neck squamous cell carcinoma, gastric cancer, breast cancer, lung cancer, colorectal cancer, and hepatocellular carcinoma cell lines. The effects of the novel chalcone-based 1 (UR-1) on CSC-associated phenotypes were evaluated in vitro and in organoid-derived xenograft models. Stemness-associated markers and apoptotic signaling were assessed via immunoblotting and immunofluorescence analyses. Structure-based analyses revealed that UR-1 favorably interacts with surface-accessible binding pockets of both CD44 and CD133, with comparable binding affinity toward the two CSC markers. Mechanistically, UR-1 markedly suppressed ERK phosphorylation (p-ERK), thereby attenuating downstream signaling associated with CSC maintenance. Consistent with these findings, UR-1 markedly suppressed the expression of stemness-associated proteins and impaired spheroid- and organoid-forming capacity in CD44 cancer cells derived from multiple tumor types. Similar inhibitory effects were observed in CD133 CSC populations derived from lung, colorectal, and liver cancers, where UR-1 reduced three-dimensional growth and stemness marker expression. In CD133 cancer organoid models, UR-1 disrupted organoid architecture and decreased the expression of CD133 and SOX2. Furthermore, UR-1 treatment markedly attenuated stemness marker expression and induced cleaved caspase-3-positive apoptotic signaling in CD44 or CD133 organoid-derived xenografts. These findings demonstrate that UR-1 suppresses stemness and promotes apoptosis in CD44 and CD133 CSC populations in association with suppression of ERK phosphorylation. By targeting this critical signaling axis, UR-1 attenuates CSC-driven tumor progression and therapeutic resistance, highlighting its potential as a promising therapeutic candidate.
STAT3 S-glutathionylation regulates Th17 differentiation in experimental immune thrombocytopenia.
Maimaiti G, Yue Y, Cheng Y … +2 more , Li D, Zhang Y
Exp Cell Res · 2026 Jul · PMID 42140306 · Publisher ↗
BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune condition marked by an abnormal response of T cells, particularly driven by splenic T helper cells under the regulation of STAT3. Protein S-glutathionylation (PS...
BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune condition marked by an abnormal response of T cells, particularly driven by splenic T helper cells under the regulation of STAT3. Protein S-glutathionylation (PSSG), a vital post-translational modification, significantly impacts the function of numerous proteins. However, the role of S-glutathionylation in modulating STAT3 activation and T helper cells in ITP has not been previously investigated. This study reveals that S-glutathionylation, regulated by the deglutathionylation enzyme glutaredoxin 1 (Grx1), is essential in the pathogenesis of ITP. METHODS: Levels of S-glutathionylation in ITP patients were evaluated using Western blotting and GSSG/GSH assay kits. To explore the role of S-glutathionylation in ITP, we employed wild-type (WT) and glutaredoxin 1 knockout (Grx1 KO) mice to create a passive ITP mouse model. The differentiation of Th17 cells was assessed both in vitro and in vivo via flow cytometry. Additionally, STAT3 activation was examined using Western blotting, GSSG assays, and immunofluorescence. RESULTS: An elevation in protein S-glutathionylation (PSSG) was observed in ITP patients. In our mouse model, Grx1 KO mice displayed higher PSSG levels, which were associated with a reduction in ITP symptoms. Mechanistically, Grx1 KO enhanced STAT3 S-glutathionylation, thereby inhibiting its activation and decreasing the production of inflammatory cytokines. Moreover, STAT3 S-glutathionylation significantly suppressed Th17 cell differentiation, underscoring its role in modulating immune responses in ITP. CONCLUSIONS: Elevated PSSG levels due to Grx1 KO enhance STAT3 S-glutathionylation, which subsequently inhibits STAT3 activation and Th17 cell differentiation, thereby alleviating ITP symptoms.
Glutathione decline coordinates mitochondria to license histone acetylation and zygotic genome activation.
Xu Y, Huang L, Wu Y … +2 more , Cai L, Zhang J
Exp Cell Res · 2026 Jul · PMID 42140305 · Publisher ↗
The glutathione (GSH) metabolism pathway plays a pivotal role in maintaining redox homeostasis, yet its coordination with mitochondrial function and reactive oxygen species (ROS) dynamics during this process remains poor...
The glutathione (GSH) metabolism pathway plays a pivotal role in maintaining redox homeostasis, yet its coordination with mitochondrial function and reactive oxygen species (ROS) dynamics during this process remains poorly defined. Here, we report that a developmentally programmed decline in endogenous GSH occurs from the zygote to the 2-cell stage, while ROS levels and mitochondrial activity remain low. Perturbation of this physiological GSH decrease-either by depletion or excessive supplementation-led to developmental arrest at the 2-cell stage, accompanied by aberrant histone acetylation, premature elevation of mitochondrial activity. Further examination revealed these interferences downregulated key zygotic genome activation (ZGA) transcription factors and mitochondrial genes. Furthermore, we show that antioxidants such as GSH, α-lipoic acid, and vitamin C can partially rescue embryonic defects induced by redox imbalance, albeit with varying efficacy. Our findings uncover GSH-mediated redox balance in regulating histone acetylation and mitochondrial maturation from the zygote to 2-cell stages, providing new insights into the metabolic-epigenetic interplay that guides early embryogenesis.
GSK3β functions as a mechanosensitive regulator that links flow stress to Shh signaling.
Dai Y, Liu Y, Xu H … +4 more , Chi Y, Chen J, Li V, Jiang Y
Exp Cell Res · 2026 Jul · PMID 42128195 · Publisher ↗
Primary cilia sense laminar flow through physical deflection, yet how this mechanical cue is translated into signaling regulation remains unclear. Here, we demonstrate that flow-induced ciliary bending promotes the accum...
Primary cilia sense laminar flow through physical deflection, yet how this mechanical cue is translated into signaling regulation remains unclear. Here, we demonstrate that flow-induced ciliary bending promotes the accumulation of GSK3β within cilia, leading to repression of Sonic Hedgehog (Shh) signaling. This response requires the tumor suppressor folliculin (FLCN). Loss of GSK3β results in ligand-independent ciliary accumulation of Smoothened (Smo) and aberrant Shh signaling. Mechanistically, GSK3β phosphorylates Smo at two sites in its C-terminal intracellular domain, and mutations at these sites enhance Smo retention within cilia. Shh stimulation induces inhibitory phosphorylation of GSK3β at T390, thereby relieving its negative regulation of Shh signaling. Together, these findings identify GSK3β as a mechanosensitive regulator that couples flow-induced ciliary bending to Shh pathway activity through control of Smo ciliary localization.
Baicalein protects human keratinocytes against PM-induced apoptosis by suppressing oxidative stress, endoplasmic reticulum stress, and ERK/JNK signaling.
Herath HMUL, Piao MJ, Kang KA … +8 more , Fernando PDSM, Senavirathna HMMM, Mahadurage PLM, Boo HJ, Yoon SP, Lee MH, Kim YR, Hyun JW
Exp Cell Res · 2026 Jul · PMID 42119881 · Publisher ↗
Excessive exposure to fine particulate matter (PM; ≤2.5 μm) induces oxidative stress through the overproduction of reactive oxygen species (ROS), ultimately leading to keratinocyte injury and apoptosis. In this study, we...
Excessive exposure to fine particulate matter (PM; ≤2.5 μm) induces oxidative stress through the overproduction of reactive oxygen species (ROS), ultimately leading to keratinocyte injury and apoptosis. In this study, we investigated whether baicalein, a flavonoid with potent antioxidant properties, protects human HaCaT keratinocytes against PM-induced endoplasmic reticulum (ER) stress-mediated apoptosis. Cells were pretreated with baicalein prior to PM exposure, and confocal microscopy, flow cytometry, and immunoblotting were used to assess cell viability, ROS generation, oxidative macromolecular damage, mitochondrial dysfunction, ER stress signaling, and apoptotic cell death. PM exposure markedly elevated intracellular ROS levels, leading to lipid peroxidation, protein carbonylation, and oxidative DNA damage, whereas baicalein pretreatment attenuated these effects and restored cell viability. Moreover, baicalein prevented PM-induced mitochondrial membrane depolarization and caspase-dependent apoptosis, as evidenced by decreased Bax, cleaved caspase-9, cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase levels, together with increased Bcl-2 expression. Additionally, baicalein effectively suppressed PM-induced intracellular Ca overload and ER stress-related signaling, including activation of protein kinase R-like ER kinase, eukaryotic initiation factor 2α, inositol-requiring enzyme 1α, activating transcription factor 6, X-box binding protein 1, C/EBP homologous protein, and 78 kDa glucose-regulated protein. Pharmacological inhibition of ER stress with tauroursodeoxycholic acid partially recapitulated the cytoprotective effects of baicalein, underscoring the importance of ER stress modulation in its protective mechanism. Furthermore, baicalein significantly inhibited PM-induced activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), two key components of the mitogen-activated protein kinase signaling cascade involved in oxidative stress-induced apoptosis. Collectively, these findings demonstrate that baicalein protects keratinocytes against PM-induced apoptosis by suppressing ROS accumulation, alleviating ER stress-associated Ca dysregulation, and inhibiting ERK/JNK-dependent apoptotic signaling.
The redox-active CXXC motif of BCAT1 regulates extracellular vesicle biogenesis in U937 macrophages.
Hillier J, Brunet MY, Terry R … +6 more , Whittaker J, Allcot G, Cox SC, Esteban P, Coles SJ, Wall I
Exp Cell Res · 2026 Jul · PMID 42114671 · Publisher ↗
Cytosolic branched-chain aminotransferase 1 (BCAT1) is a canonical transaminase that catalyses the breakdown of essential amino acids, including leucine, isoleucine and valine. Our previous work showed that BCAT1 also co...
Cytosolic branched-chain aminotransferase 1 (BCAT1) is a canonical transaminase that catalyses the breakdown of essential amino acids, including leucine, isoleucine and valine. Our previous work showed that BCAT1 also contains a redox-active CXXC motif with antioxidant activity, reducing intracellular reactive oxygen species (ROS) in the monocytic U937 cell line. Moreover, these cells display decreased expression of CD14/CD68 compared to controls, a phenotype indicative of M2 macrophage polarisation. Given that Extracellular Vesicle (EV) release is associated with oxidative stress, and that there is increasing interest in the therapeutic use of M1-and M2-derived macrophage EVs, we investigated whether the BCAT1 CXXC motif could modulate EV release in U937 cells constitutively overexpressing WT BCAT1, a CXXC motif mutant (CXXS BCAT1), or vector control. Here, we show that whilst WT BCAT1 cells display significantly lower intracellular ROS compared to controls, nanoparticle tracking analysis demonstrates that WT BCAT1 significantly increases EV generation compared to CXXS BCAT1 and vector controls under both normal (10% FBS) and serum-starved (0% FBS) conditions. Analysis of CD63/CD81/CD9 tetraspanin composition revealed that the majority of EVs produced were CD63, with serum starvation further increasing CD63 EV abundance. Taken together, these data indicate that BCAT1, and its redox-active CXXC motif, may play a novel role in EV biogenesis in macrophage-like cells.
Tsc1 and Tsc2 maintain hematopoietic homeostasis through multiple signaling pathways in Drosophila.
Wei Z, Wang H, Zhai C … +2 more , Jin LH, Yu S
Exp Cell Res · 2026 Jul · PMID 42103268 · Publisher ↗
The lymph gland is the main hematopoietic tissue in Drosophila larvae, regulated by multiple signaling pathways and serving as a valuable genetic model for studying hematopoiesis. Investigating hematopoietic mechanisms i...
The lymph gland is the main hematopoietic tissue in Drosophila larvae, regulated by multiple signaling pathways and serving as a valuable genetic model for studying hematopoiesis. Investigating hematopoietic mechanisms in Drosophila can provide valuable insights into the pathogenesis of human hematopoietic malignancies. Tsc1 and Tsc2 are tumor suppressor genes mutated in tuberous sclerosis complex, a tumor syndrome. The protein complexes formed by their gene products have attracted considerable interest in the field of signaling research. However, their roles in maintaining hematopoietic homeostasis remain unclear. In this study, we found that knockdown of Tsc1 or Tsc2 in the intermediate zone and cortical zone leads to increased proliferation and differentiation of hemocytes, accompanied by disruption of progenitor cell maintenance in the medullary zone. Aberrant differentiation of lamellocytes was also observed, along with a marked increase in both the size and number of circulating hemocytes. Furthermore, Tsc1 or Tsc2 knockdown elevated levels of cell death in both the lymph gland and circulating hemocytes. Our findings suggest that Tsc1 and Tsc2 play multifaceted roles in regulating hematopoietic homeostasis through the TOR and Notch signaling pathways. Additionally, Tsc2 contributes to hematopoietic regulation via the JNK pathway and is also involved in apoptosis regulation. In conclusion, our findings revealed that Tsc1 and Tsc2 function within the intermediate zone and cortical zone of the lymph gland to maintain hematopoietic homeostasis through multiple signaling pathways.
The in vitro acquisition of CD11a by gastric cancer cells after contact with T cells via trogocytosis increases adhesion to endothelial cells.
Miyato H, Saito S, Ohzawa H … +7 more , Yamaguchi H, Kawahira H, Horie H, Hosoya Y, Mimura T, Sata N, Kitayama J
Exp Cell Res · 2026 Jul · PMID 42097441 · Publisher ↗
BACKGROUND: Recent studies reveal that during trogocytosis plasma membranes are frequently transferred upon cell-to-cell contact, and that this phenomenon plays an important role in the modulation of anti-tumor immune re...
BACKGROUND: Recent studies reveal that during trogocytosis plasma membranes are frequently transferred upon cell-to-cell contact, and that this phenomenon plays an important role in the modulation of anti-tumor immune response. However, the accompanying physiological roles in the tumor microenvironment are poorly understood. METHODS & RESULTS: Human gastric cancer cell line OCUM-1 was co-cultured with T cells whose plasma membrane was stained with PKH26. Flow-cytometric analysis revealed that OCUM-1 was positive for PKH26 at 1 h and the positive rate increased over time. The acquisition of PKH26 was dependent on cell-to-cell contact and suppressed when T cells were fixed. OCUM-1 came to express various immunological synapse molecules after 10 h of co-culture (positive rate, CD45:73.6 ± 7.9%, CD3: 35.5 ± 10.1%, CD4: 15.3 ± 14.7%, CD8: 7.7 ± 2.4%, CD11a: 8.1 ± 4.3%, CD11b: 3.4 ± 1.9%). We focused on CD11a which belongs to β2 integrins and aids immune cell adherence to endothelial cells. After co-culture with activated T cells (LAK), the expression level of CD11a on OCUM-1 was accelerated (with T cells: 19.1 ± 13.4%, with LAK: 75.2 ± 11.8%) and the adhesion rate on endothelial cells increased in a CD11a dependent manner (adhesion rate, single-culture: 2.0 ± 0.64%, co-culture: 6.3 ± 2.0%, co-culture (pre-treat with CD11a antibody): 2.3 ± 1.4%, n = 10, single-culture vs co-culture, p < 0.0001; co-culture vs pre-treat with CD11a antibody, p < 0.0001). CONCLUSION: These results suggest that acquisition of CD11a from T cells by trogocytosis enables cancer cells to increase adhesive properties towards endothelial cells, which may result in intravenous metastasis promotion.
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