Experimental Cell Research[JOURNAL]
Sun
200 papers
H3K27 acetylation activated-CYP1B1 promotes invasion, migration and radioresistance in gastric cancer via p38 MAPK-mediated fatty acid metabolism.
Chen Z, Lv J, Song L … +1 more , Liu Y
Exp Cell Res · 2026 May · PMID 41833880 · Publisher ↗
INTRODUCTION: Gastric cancer (GC) is the fifth commonest malignant tumor in the world and ranks third in all cancer-related deaths. Patients suffering from advanced GC have poor prognosis due to metastasis and the resist...
INTRODUCTION: Gastric cancer (GC) is the fifth commonest malignant tumor in the world and ranks third in all cancer-related deaths. Patients suffering from advanced GC have poor prognosis due to metastasis and the resistance to radiotherapy. The current study aims to investigate the specific role of cytochrome P450 1B1 (CYP1B1) in the metastasis and radioresistance of GC cells. METHODS: RNA expression profiles in the blood samples of GC patients with or without peritoneal metastasis were screened from the gene expression omnibus database. The prognostic value of CYP1B1 was analyzed using Gene Expression Profiling Interactive Analysis and University of ALabama at Birmingham CANcer databases. The mRNA and protein levels were detected by RT-qPCR and Western blot, respectively. Transwell and wound healing assays were applied to measure the invasive and migratory abilities of GC cells. Clonogenic survival assay was conducted to evaluate the radioresistance of GC cells. Chromatin immunoprecipitation and luciferase reporter assays were performed to analyze the H3K27ac enrichment of CYP1B1 promoter. Co-immunoprecipitation assay was conducted to demonstrate the interaction between CYP1B1 and ARNT. In vivo experiments were performed to validate the effect of CYP1B1 silencing on the radioresistance of GC cells in vivo. RESULTS: CYP1B1 was significantly upregulated in the blood samples of GC patients with peritoneal metastasis. Both mRNA and protein levels of CYP1B1 were elevated in highly metastatic GC cells. Knockdown of CYP1B1 repressed the invasive and migratory abilities of highly metastatic GC cells and decreased radioresistance. Mechanistically, YY1/p300 transcription complex enhanced the H3K27 acetylation level in CYP1B1 promoter. CYP1B1 interacted with ARNT to activate p38 MAPK pathway. Rescue experiments showed that ARNT overexpression abolished the suppressive effect of CYP1B1 knockdown on the invasion, migration and radioresistance of highly metastatic GC cells. In vivo experiments validated that CYP1B1 silencing reduced the radioresistance of GC cells in vivo. CONCLUSION: H3K27ac-induced upregulation of CYP1B1 promoted the invasion, migration and radioresistance of GC cells by facilitating p38 MAPK-mediated fatty acid metabolism. Our findings suggest that CYP1B1 may serve as a therapeutic target to overcome metastasis and radioresistance in GC.
TRPV4-dependent PI3K-Akt activation mediates hyperosmotic stress-induced cell contraction and myofibroblast differentiation in tubular epithelial cells.
Miyano T, Sakamoto N, Sera T
Exp Cell Res · 2026 May · PMID 41825809 · Publisher ↗
The osmotic environment surrounding the tubular epithelial cells fluctuates drastically. We have demonstrated that sustained hyperosmotic stress in tubular epithelial cells induces epithelial-mesenchymal transition, and...
The osmotic environment surrounding the tubular epithelial cells fluctuates drastically. We have demonstrated that sustained hyperosmotic stress in tubular epithelial cells induces epithelial-mesenchymal transition, and that cell contraction induced by hyperosmotic stress is essential for their differentiation into α-smooth muscle actin (α-SMA)-positive myofibroblasts. However, the mechanism linking hyperosmolarity-induced cell contraction to the differentiation of epithelial cells into α-SMA-positive myofibroblasts remains unclear. To elucidate the mechanisms underlying hyperosmotic contraction in NRK-52E cells, we conducted a targeted pharmacological screening of mechanosensitive receptor modulators, identifying transient receptor potential vanilloid 4 (TRPV4) channel antagonists (HC-067047, RN-1665, and GSK205) as potent inhibitors of cell contraction in response to 200 mM mannitol, highlighting TRPV4 as a key upstream mechanosensor. We performed RNA sequencing to profile gene expression under hyperosmotic stress. Using Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, we identified 3137 differentially expressed genes (adjusted p < 0.05, |log2FoldChange| > 1), which were most significantly enriched in the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway, exhibiting the highest gene ratio. Finally, to connect the mechanosensor to this pathway, we focused on TRPV4 and PI3K-Akt signaling. Hyperosmotic stress increased Akt phosphorylation, which was suppressed by TRPV4 inhibition. TRPV4 or PI3K inhibition reduced α-SMA expression and attenuated the upregulation of extracellular matrix-related genes, indicating that TRPV4-mediated activation of the PI3K-Akt pathway drives α-SMA-positive myofibroblast differentiation. Collectively, the pharmacological and transcriptomic analyses identified TRPV4-dependent PI3K-Akt activation as the central driver of osmotic stress-induced contraction and myofibroblast differentiation.
KRT15 drives immunosuppression in esophageal squamous cell carcinoma through GSK3β/β-catenin/CD276 signaling.
Yang C, Zhong Z, Li C … +4 more , Wang H, Chen L, Jiang J, Wu C
Exp Cell Res · 2026 May · PMID 41819470 · Publisher ↗
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly aggressive disease that carries a poor prognosis and limited therapeutic efficacy, particularly in advanced stages. While immune checkpoint inhibitors (IC...
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly aggressive disease that carries a poor prognosis and limited therapeutic efficacy, particularly in advanced stages. While immune checkpoint inhibitors (ICIs) have improved outcomes in some patients, resistance mechanisms remain poorly understood. Keratin 15 (KRT15) has been implicated in tumor progression and immune regulation, yet its role in ESCC immunotherapy resistance is unclear. METHODS: Transcriptome data from 12 ESCC patients receiving neoadjuvant chemoimmunotherapy (NACI) were analyzed, categorizing them into pathologic complete response (pCR) and non-pCR groups. An independent tissue microarray (TMA) of 102 patients was used to assess KRT15 expression and prognosis. Bioinformatics, immunohistochemistry, and immunofluorescence were employed to validate findings, followed by functional validation. RESULTS: KRT15 was significantly overexpressed in non-pCR patients and ESCC tissues, correlating with poor prognosis. Genetic silencing of KRT15 enhanced tumor sensitivity to immunotherapy, with increased intratumoral CD8 T cells and NK cells, and reduced CD276 expression. Mechanistically, KRT15 interacted with GSK3β to stabilize β-catenin, promoting CD276 transcription and suppressing NK cell function. Rescue experiments confirmed that CD276 overexpression or GSK3β inhibition reversed these effects. CONCLUSION: KRT15 regulated GSK3β phosphorylation to promote β-catenin stability and CD276 expression, thereby inhibiting NK cell function and contributing to immune resistance in ESCC.
CD73 mesenchymal stem cell (MSC) transplantation improves pressure ulcer healing by promoting angiogenesis through the HIF-1α/VEGF pathway in diabetic mice.
Hou H, Zhang D, Wang S … +7 more , Zheng M, Bai X, Wang G, Xu X, Guo Z, Li Z, Li Q
Exp Cell Res · 2026 May · PMID 41819469 · Publisher ↗
Diabetic wound healing remains a major clinical challenge. Although therapies based on mesenchymal stem cells (MSCs) have emerged as promising strategies to address this impairment, the specific contribution of CD73 expr...
Diabetic wound healing remains a major clinical challenge. Although therapies based on mesenchymal stem cells (MSCs) have emerged as promising strategies to address this impairment, the specific contribution of CD73 expression to the therapeutic potential of MSCs has not been previously explored. In this study, we explored the role of CD73 expression in the therapeutic potential of human adipose tissue-derived mesenchymal stem cells (hADMSCs) for treating diabetic pressure ulcers in a mouse model. Our findings demonstrated that CD73-positive hADMSCs (CD73hADMSCs) could promote enhanced wound healing in diabetic mice and mitigate the endothelial dysfunction caused by high glucose levels. Conversely, inhibition of CD73 impairs these therapeutic effects. CD73 could modulate vascular endothelial growth factor A (VEGFA) expression under hypoxic conditions via a hypoxia-inducible factor-1α (HIF-1α)-dependent pathway. Furthermore, CD73 expression was shown to regulate the activation of the PI3K/Akt signaling pathway, contributing to accelerated wound closure in diabetic pressure ulcer mice. These findings provide new insights into the potential of MSC-based therapies for treating conditions marked by immune dysregulation and impaired vascularization, including metabolic and ischemic diseases.
Loss of splicing factor RBM25 promotes the collapse of murine hematopoiesis.
Pereira MA, Schuster MB, Tapia M … +3 more , Aragon-Fernandez P, Schoof EM, Porse BT
Exp Cell Res · 2026 May · PMID 41819468 · Publisher ↗
Whilst pre-mRNA splicing has been demonstrated to play functional roles in normal hematopoiesis, the potential importance of many splicing regulators remains unexplored. RNA-binding motif protein 25, (RBM25), is a splici...
Whilst pre-mRNA splicing has been demonstrated to play functional roles in normal hematopoiesis, the potential importance of many splicing regulators remains unexplored. RNA-binding motif protein 25, (RBM25), is a splicing factor involved in multiple cellular functions, such as proliferation and apoptosis, in various tissues as well as in leukemia. Here, we use a conditional knock-out model to show that the fundamental role of RBM25 in alternative splicing is reflected in the pivotal role of the protein for multiple hematopoietic lineages, including long-term hematopoietic stem cells, as well as embryonic stem cells derived from gene targeted mice. In contrast, mono-allelic deletion of Rbm25 did not impair HSC self-renewal or differentiation, neither under steady-state conditions nor after proliferative stress induced by bone marrow transplantation. Thus, we demonstrate that Rbm25 is haplosufficient and required for the maintenance of normal murine hematopoiesis.
Microbiota metabolite lithocholic acid in cancer: Mechanisms and therapeutic potential.
Darmadi D, Muhamed AJ, Gerasimov SG … +2 more , Mirzaei R, Karampoor S
Exp Cell Res · 2026 Jul · PMID 41802534 · Publisher ↗
The human gut microbiome is centrally implicated in host disease and health control via the production of a range of bioactive metabolites. Of these, lithocholic acid (LCA), a derivative of microbial metabolism secondary...
The human gut microbiome is centrally implicated in host disease and health control via the production of a range of bioactive metabolites. Of these, lithocholic acid (LCA), a derivative of microbial metabolism secondary bile acid, has received attention owing to its multifaceted functions in cancer. LCA, a hydrophobic microbiota-derived bile acid, was implicated in carcinogenicity and hepatotoxicity even in the ancient era. In this sense, studies have found a contrasting role of LCA as a tumor promoter or tumor suppressor based on the molecular environment and type of tumor. Antitumor effects of LCA have also been observed in various cancers such as breast, prostate, colon, and neuroblastoma. Interestingly, LCA induces selective apoptosis of cancer cells through intrinsic and extrinsic pathways but without damaging normal cells, and the process is partly caspase-dependent. Mechanistically, LCA induces endoplasmic reticulum (ER) stress response, induces autophagy in certain cancer cell lines, and inhibits mitochondrial function, all contributing to its cytotoxic effect. It also causes oxidative and nitrosative stress through downregulation of nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1(Keap1) pathway and induction of inducible nitric oxide synthase (iNOS) mediated through TGR5 and Chimeric antigen receptor (CAR) receptor activation. Besides its cytostatic action on itself, LCA was determined to have the capability to modulate the tumor microenvironment through immunomodulation and anti-inflammation, which are behind its therapeutic actions. Via its action on nuclear receptors like the vitamin D receptor (VDR), LCA has been shown to inhibit proteasome activity, create pores in membranes, and alter calcium uptake and epithelial integrity under conditions of oxidative stress. Because of its selective anticancer action, receptor-mediated signal activity, and microbiota origin, LCA is a good cancer drug candidate. This review discusses primarily the molecular processes through which LCA regulates cancer pathogenesis and determines its therapeutic potential based on preclinical and clinical data.
PEX5 integrates the p38 MAPK signaling pathway and taurine metabolism to regulate senescence in lung fibroblasts.
Zheng L, Huang X, Peng Z … +4 more , Qian S, Lu Y, Lin L, Su X
Exp Cell Res · 2026 May · PMID 41794210 · Publisher ↗
Chronic lung diseases are a growing global health burden in aging populations, yet their underlying mechanisms remain poorly defined, and current treatment options are limited. Cellular senescence, a hallmark of aging, i...
Chronic lung diseases are a growing global health burden in aging populations, yet their underlying mechanisms remain poorly defined, and current treatment options are limited. Cellular senescence, a hallmark of aging, is increasingly recognized as a key driver of chronic lung pathology and is often accompanied by dysfunction in subcellular organelles. Among these, peroxisomes have emerged as important regulators, though their specific roles in senescence remain underexplored. To address this gap, we investigated the function of peroxisomes during replicative and oxidative stress-induced senescence in human fetal lung fibroblasts (HFL-1). We found that peroxisomal biogenesis, including the import receptor PEX5 expression, is significantly downregulated in senescent cells. Loss of PEX5 activated p38 mitogen-activated protein kinase (p38 MAPK) signaling, reduced nuclear translocation of the transcription factor EB (TFEB), and impaired autophagic flux, thereby promoting a pro-senescent cellular state. Metabolomic profiling revealed that PEX5 overexpression enhanced taurine biosynthesis by facilitating the peroxisomal localization of its key synthetic enzymes. Remarkably, exogenous taurine supplementation restored PEX5 levels in senescent fibroblasts and aged mouse lungs, mitigating senescence phenotypes and establishing a PEX5-taurine-PEX5 positive feedback loop. Together, these findings delineate a novel peroxisome-centered regulatory mechanism that integrates p38 MAPK-TFEB signaling and taurine metabolism to control cellular senescence. This work provides new insights into the interplay between organelle function and aging and highlights potential targets for therapeutic intervention in age-related lung diseases.
Tumor-suppressive SQLE reprograms metabolic flux: Convergence of aerobic glycolysis and cholesterol pathways in ovarian cancer.
He F, Ma S, Fu J … +5 more , Chang S, Wang R, Chen H, Li X, Zhao L
Exp Cell Res · 2026 May · PMID 41791570 · Publisher ↗
Squalene epoxidase (SQLE) exerts anti-ovarian cancer (OC) role, but its mechanistic basis remains to be defined. Through integrated bioinformatic analysis and immunohistochemistry, SQLE protein expression was found highl...
Squalene epoxidase (SQLE) exerts anti-ovarian cancer (OC) role, but its mechanistic basis remains to be defined. Through integrated bioinformatic analysis and immunohistochemistry, SQLE protein expression was found highly expressed in OC tissue compared to normal ovarian tissue, however, using the stable/transient SQLE knockdown and overexpression OC cell models, the cell proliferation and metabolism assays revealed SQLE knockdown enhanced, while SQLE overexpression suppressed cell proliferation, total/free cholesterol level, glycolytic flux and hexokinase Ⅱ (HK2) expression. SQLE positively regulated farnesyl-diphosphate farnesyltransferase 1 (FDFT1) expression. These results showed SQLE reprogramed cellular cholesterol homeostasis and aerobic glycolytic metabolism, and exerted tumor-suppressive effects in OC cells, providing a new insight for OC treatment.
Endothelial lncRNA-HOXA responses to combined chemical hypoxia and shear stress.
Gomes AM, de Almeida GS, Pinto TS … +2 more , Teixeira SA, Zambuzzi WF
Exp Cell Res · 2026 Apr · PMID 41775286 · Publisher ↗
Endothelial cells respond to changes in oxygen availability and mechanical forces by adjusting their transcriptional and secretory profiles, thereby shaping vascular and tissue-level adaptation. In this study, primary hu...
Endothelial cells respond to changes in oxygen availability and mechanical forces by adjusting their transcriptional and secretory profiles, thereby shaping vascular and tissue-level adaptation. In this study, primary human endothelial monolayers were exposed to a chemical hypoxia mimic under static or shear-stress conditions, using a viability-guided experimental design to define non-cytotoxic exposure parameters. Under these conditions, hypoxia-associated responses were observed together with coordinated changes in long non-coding RNAs linked to the HOX genomic region, including HOTAIR and HOTTIP, and in selected members of the HOXA gene cluster. Transcripts related to Notch and BMP signaling showed increased expression, whereas components of the canonical Wnt pathway displayed reduced or stable expression, consistent with a context-dependent transcriptional profile rather than a generalized activation of proliferative programs. Endothelial migration was also altered in scratch-wound assays. Extracellular vesicles released under static and shear-stress conditions exhibited physical characteristics consistent with small vesicle populations, and their RNA cargo reflected transcriptional changes associated with hypoxia and mechanical exposure. Together, these findings provide a descriptive cellular and vesicular framework for how endothelial cells integrate chemical hypoxia and shear stress at the transcriptional and intercellular communication levels. Thus, this work establishes a basis for future functional studies aimed at testing the causal roles of long non-coding RNAs and vesicle-mediated signaling in vascular-stromal interactions within hypoxic and mechanically dynamic tissue microenvironments.
Phenylacetylglutamine is associated with diabetic retinopathy via transgelin-mediated ferroptosis in hyperglycemic retinal epithelial cells.
Hu S, Yu P, Zhang J … +2 more , Yan Z, Liu Z
Exp Cell Res · 2026 Apr · PMID 41765161 · Publisher ↗
Hyperglycemia is a pivotal risk factor in the pathogenesis of diabetic retinopathy (DR), with accumulating evidence implicating the intestinal microbial metabolite phenylacetylglutamine (PAGln) in disease progression. Ho...
Hyperglycemia is a pivotal risk factor in the pathogenesis of diabetic retinopathy (DR), with accumulating evidence implicating the intestinal microbial metabolite phenylacetylglutamine (PAGln) in disease progression. However, the precise mechanisms underlying PAGln's role in DR remain incompletely understood. This study aimed to investigate the effects of PAGln on hyperglycemia-induced retinal pigment epithelial (RPE) cell dysfunction, with a focus on ferroptosis as a potential mechanistic pathway. Clinical analysis via enzyme-linked immunosorbent assay (ELISA) revealed significantly elevated serum PAGln levels in DR patients compared to healthy controls (11.09 ± 9.80 vs. 2.75 ± 2.56 nmol/mL, P < 0.01), which exhibited a strong correlation with oxidative stress markers (MDA, HO) and disease severity. An in vitro DR model was established by exposing ARPE-19 cells to high glucose (HG), followed by PAGln treatment. Comprehensive analyses demonstrated that PAGln exacerbated oxidative stress (elevated ROS and MDA, reduced GSH/SOD), induced iron overload (Fe), promoted lipid peroxidation, and suppressed GPX4 expression, all hallmark features of ferroptosis. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, mitigated these effects, restoring cellular viability and GPX4 levels. Integrative mechanistic studies, including RNA sequencing and RT-qPCR, identified transgelin (TAGLN) as a critical mediator upregulated by PAGln. Knockdown of TAGLN alleviated ferroptosis, reduced oxidative damage, and restored cellular viability. Collectively, these findings suggest a potential involvement of the PAGln-TAGLN-ferroptosis pathway in DR progression, providing new insights into the metabolic regulation of retinal degeneration and potential therapeutic targets.
Differential regulation of EMT-related pathways by inflammatory microenvironment in 3D prostate spheroids and tumor-stroma interaction models.
Calisir FGA, Arziman S, Isel E … +1 more , Debelec Butuner B
Exp Cell Res · 2026 Apr · PMID 41765160 · Publisher ↗
Chronic inflammation plays a major role in the initiation, progression, and metastasis of prostate cancer (PCa) by driving tumorigenic processes such as Epithelial-Mesenchymal Transition (EMT). To investigate these mecha...
Chronic inflammation plays a major role in the initiation, progression, and metastasis of prostate cancer (PCa) by driving tumorigenic processes such as Epithelial-Mesenchymal Transition (EMT). To investigate these mechanisms in physiologically relevant settings, we optimized two complementary in vitro tumor models: 3D prostate spheroids that mimics multicellular interactions and an epithelial-myofibroblast co-culture system that reflects key tumor-stroma dynamics under inflammatory conditions. Our optimization revealed that successful spheroid formation depends on cell line-specific molecular features rather than a universal spheroid size. Compared with conventional 2D cultures, inflammatory stimuli modulated EMT mediators significantly in a cell line-dependent manner; notably, fibronectin, vimentin, and TWIST1 were differentially regulated in 3D spheroids, indicating enhanced invasive features driven by inflammatory cues. The co-culture model successfully represented reactive stroma formation, and stromal influence dramatically shaped inflammation-induced anoikis resistance and cell migration. Overall, our findings demonstrated that tumor-stroma interactions critically contribute to the impact of inflammation on EMT in PCa. Our optimized 3D spheroid and co-culture models provide a robust and powerful platform to unravel the functional consequences of inflammation and offer mechanistic insight into cellular processes underlying PCa progression, supporting the development of targeted therapeutic strategies.
Cadherin-26 contributes to an M2-like macrophage polarization and TGF-β1 expression via the CTNNB1-STAT3 axis in interstitial lung disease.
Chen G, Huang C, Wang Z … +8 more , Gu W, Jie H, Xiong T, Liu Y, Feng Y, Yi L, Xue Z, Zhen G
Exp Cell Res · 2026 Apr · PMID 41763513 · Publisher ↗
Interstitial lung disease (ILD) is a heterogeneous group of diseases characterized by inflammation and interstitial fibrosis of the pulmonary parenchyma. Alternative activation of macrophages can promote fibrosis through...
Interstitial lung disease (ILD) is a heterogeneous group of diseases characterized by inflammation and interstitial fibrosis of the pulmonary parenchyma. Alternative activation of macrophages can promote fibrosis through the secretion of TGF-β1 in ILD. However, the mechanisms regulating alternative macrophage activation and TGF-β1 expression in ILD patients remain unclear. We demonstrated that cadherin-26 (CDH26) expression is upregulated in ILD patients' lungs and inversely correlated with lung function. CDH26 is predominantly expressed in macrophages in bronchoalveolar lavage cells from ILD patients. In a mouse model of bleomycin-induced pulmonary fibrosis, we found that macrophage-specific Cdh26 deficiency significantly attenuated bleomycin-induced fibrosis, collagen deposition, alternative activation-associated (M2-like) macrophage polarization, and Tgf-β1 expression. In vivo and vitro experiments showed that Cdh26 deficiency was associated with suppression of the Ctnnb1-Stat3 signaling axis in macrophages. Our study delineates a novel CDH26-mediated signaling in lung fibrosis, and CDH26 may represent a potential therapeutic target for ILD.
Rab35 drives the malignant progression of endometrial carcinoma by regulating the nuclear translocation of β-catenin.
Yang E, Wang Y, Mao W … +8 more , Cui T, Li M, Zhao S, Zhang J, Yan Y, Chen Y, Tian W, Wang Y
Exp Cell Res · 2026 May · PMID 41763512 · Publisher ↗
BACKGROUND: Endometrial carcinoma (EC) is a common malignancy of the female reproductive system. Rab35 is widely recognized as an oncogenic driver and has been implicated in the progression of various malignant tumors. H...
BACKGROUND: Endometrial carcinoma (EC) is a common malignancy of the female reproductive system. Rab35 is widely recognized as an oncogenic driver and has been implicated in the progression of various malignant tumors. However, its regulatory mechanism and pathobiological roles in EC remain unclear. METHODS: Rab35 expression in EC was systematically profiled via integrative analysis of clinical endometrial specimens and multi-omics databases (CPTAC and GEO). The association between clinical prognosis and Rab35 expression was examined using Kaplan-Meier analysis. Mechanistic investigations included transwell assays, western blotting, and immunofluorescence in Rab35-overexpressing and CRISPR/Cas9-mediated Rab35-knockout EC cells. A mouse xenograft tumor model was established to confirm the effects of Rab35 in vivo. RESULTS: The Rab35 content increased gradually from normal endometrium to atypical hyperplastic endometrium to EC. Moreover, the findings indicated that elevated Rab35 expression was significantly associated with advanced disease characteristics and poor overall survival in patients with EC. In addition, Rab35 enhanced the migratory and invasive nature of EC cells. The expression of Rab35 was inversely linked to that of the β-catenin destruction complex-related proteins Axin-1 and GSK3β, leading to the increased nuclear translocation of β-catenin in EC cells. Animal experiments further verified that Rab35 augmented EC progression by regulating the nuclear translocation of β-catenin. CONCLUSIONS: The study revealed that high expression of Rab35 was strongly correlated with EC progression and a poor clinical outcome. Furthermore, Rab35 promoted EC cell metastasis by accelerating the nuclear translocation of β-catenin. These findings suggest that Rab35 serves as a valuable biomarker and therapeutic target for EC.
Reprogramming of astrocytes into motoneuron-like cells by a Ascl1-Myt1l-Pou3f2-Isl1 cocktail.
Yang R, Shen J, Jin P … +7 more , Yao Q, Chen S, Wu T, Chang S, Pan J, Chen Y, Chen G
Exp Cell Res · 2026 Apr · PMID 41763511 · Publisher ↗
Reprogramming of spinal astrocytes into motor neurons holds great promise for spinal cord injury in regeneration medicine. Here we identified a set of four transcription factors-achaete-scute complex homolog-like 1, myel...
Reprogramming of spinal astrocytes into motor neurons holds great promise for spinal cord injury in regeneration medicine. Here we identified a set of four transcription factors-achaete-scute complex homolog-like 1, myelin transcription factor 1 like, POU class 3 homeobox 2, and ISL LIM homeobox 1-collectively referred to as the 4 F cocktail. The 4 F cocktail reprograms rat and human reactive astrocytes into motoneuron-like cells. The reprogrammed cells display neuronal morphology and stain positive for microtubule-associated protein 2 (MAP2), a neuronal-specific marker, and choline acetyltransferase, which is a known motor neuron-specific marker. Early in the process of astrocytic reprogramming mediated by the 4 F cocktail, quantitative real-time reverse transcription polymerase chain reaction revealed that the expression of the astrocytic gene glial fibrillary acidic protein was inhibited. Additionally, the expression of the neural progenitor cell markers SRY-box transcription factor 2 and neural cell adhesion molecule 1 was upregulated within 5 days, while the motor neuron progenitor marker oligodendrocyte transcription factor 2 was activated within 7 days. Furthermore, the expression of the neural genes Map2, synapsin I, tubulin β-3, and neurofilament heavy, as well as the motor neural genes ISL LIM homeobox 1, motor neuron and pancreas homeobox 1, LIM homeobox 1, LIM homeobox 3, and NK6 homeobox 1, and survival of motor neuron 1 increased in the reprogrammed cells after induction with the 4 F cocktail. More importantly, 4 F cocktail-reprogrammed motoneuron-like cells can release acetylcholine and exhibited vulnerability to glutamate-induced excitotoxicity. Our findings demonstrate that the 4 F cocktail first reprograms spinal astrocytes into a neural progenitor-like and motor neuron progenitor-like intermediate plastic state, which then gives rise to motoneuron-like cells.
α-synuclein preformed fibrils suppress cell cycle progression and glycolytic flux in glioblastoma cells.
Song HJ, Park H, Lee E … +6 more , Kim HJ, Kim TJ, Joo BK, Byun JS, Kim S, Kim DY
Exp Cell Res · 2026 Apr · PMID 41759706 · Publisher ↗
Aging-related diseases, including cancer and neurodegenerative disorders, exhibit complex interrelationships. While Parkinson's disease (PD) and glioblastoma (GBM) both affect the central nervous system, they are pathoph...
Aging-related diseases, including cancer and neurodegenerative disorders, exhibit complex interrelationships. While Parkinson's disease (PD) and glioblastoma (GBM) both affect the central nervous system, they are pathophysiologically distinct, with an inverse correlation in their incidence. However, mechanisms underlying this inverse relationship remain poorly understood. Here, we investigate the effects of α-synuclein preformed fibrils (PFF) on GBM cells to explore potential link between neurodegenerative diseases and malignancies. PFF exerted anti-tumor activity through cyclin D1 downregulation, leading to G1 cell cycle arrest. Notably, PFF treatment significantly reduced glycolytic flux while sparing mitochondrial oxidative phosphorylation, indicating selective metabolic disruption. Furthermore, PFF inhibited the AKT signaling pathway, resulting in FOXO1 upregulation, which further contributed to its anti-tumor effects. Our findings provide novel insights into the metabolic and molecular impacts of α-synuclein aggregation on GBM, offering a potential mechanistic link between neurodegenerative processes and tumor suppression.
Transcriptomic analysis of cells following decreased mitochondrial DNA-copy number reveals compensatory mechanisms in mitochondrial DNA replication and cellular energetics.
Xie J, Win PW, Newcomb C … +3 more , Zeng S, Castellani CA, Arking DE
Exp Cell Res · 2026 May · PMID 41759705 · Full text
Mitochondrial DNA copy number (mtDNA-CN) is a metric of mitochondrial function that has been associated with a variety of diseases including cardiovascular disease and all-cause mortality. To investigate genes and pathwa...
Mitochondrial DNA copy number (mtDNA-CN) is a metric of mitochondrial function that has been associated with a variety of diseases including cardiovascular disease and all-cause mortality. To investigate genes and pathways affected by mtDNA-CN variation, we perturbed HEK 293T cells with ethidium bromide to deplete mtDNA. Using RNASeq and methylation microarrays, we evaluated transcriptomic and methylomic changes in treated cell lines. We observed an 8-fold decrease in mtDNA-CN and compensatory shifts in mitochondrial transcription to support mtDNA replication. Nuclear transcriptomic and methylomic analysis highlighted changes in metabolic pathways, including oxidative phosphorylation and canonical glycolysis. Longitudinal analyses revealed that the identified genes and pathways have different response timing, with nuclear response lagging behind mitochondrial response. These findings further elucidate the mechanisms behind mtDNA maintenance and responses to cellular energetics as well as mitochondrial-nuclear crosstalk dynamics.
Time-dependent imprinting of gut homing receptors on lymphocytes by migratory antigen presenting cells.
Barrios BE, Jaime C, Piqueras VA … +3 more , Nazar FN, Novotny Nuñez I, Correa SG
Exp Cell Res · 2026 Apr · PMID 41759704 · Publisher ↗
Circadian rhythms synchronize many physiological and immune processes, but their role in coordinating intestinal lymphocyte trafficking remains unclear. Here, we investigated the temporal regulation of gut homing recepto...
Circadian rhythms synchronize many physiological and immune processes, but their role in coordinating intestinal lymphocyte trafficking remains unclear. Here, we investigated the temporal regulation of gut homing receptors, α4β7 integrin and CCR9 chemokine receptor, on lymphocyte subsets and the involvement of migratory antigen presenting cells 5r4 in this process. Using wild-type and Period 2 (Per2) knockout mice, we analyzed receptor expression on CD4, CD8, and B lymphocytes from mesenteric lymph nodes (MLNs) at four Zeitgeber times (ZT5, ZT11, ZT17, ZT23). We observed circadian oscillations in homing receptor expression, with peaks at ZT5 in T cells and at ZT11-17 in B cells. Disruption of light-dark cycles increased α4β7 and CCR9 expression, particularly in B lymphocytes, highlighting their sensitivity to circadian misalignment. Migratory APCs isolated from afferent lymphatics showed time-dependent variation in their capacity to induce these receptors on naïve CD4Foxp3 T cells in co-culture, correlating with elevated β-catenin and transforming growth factor-beta (TGF-β) levels. In Per2 knockout mice, this circadian pattern was impaired. Multivariate analysis revealed three distinct temporal phenotypes of homing receptor expression. These findings indicate that circadian rhythms modulate lymphocyte gut homing via migratory APC function, and disruptions in circadian cues could contribute to altered mucosal immune responses in intestinal diseases.
Molecular basis of muscle wasting and emerging therapeutic strategies targeting degenerative muscle disorders.
Jude M, Rajasingh S, Alway S … +1 more , Rajasingh J
Exp Cell Res · 2026 Apr · PMID 41759703 · Full text
Muscle degenerative conditions, including sarcopenia, muscular dystrophies, and trauma-induced muscle loss, severely compromise mobility, metabolism, and overall health. These disorders result from multifactorial causes...
Muscle degenerative conditions, including sarcopenia, muscular dystrophies, and trauma-induced muscle loss, severely compromise mobility, metabolism, and overall health. These disorders result from multifactorial causes such as imbalances in protein homeostasis, satellite cell dysfunction, mitochondrial stress, and chronic inflammation. Central molecular regulators such as FOXO, AMPK, mTOR, and the myostatin/SMAD axis, play pivotal roles in driving muscle atrophy. Current regenerative strategies seek to restore muscle structure and function through stem cell-based therapies (MSCs, iPSC-derived muscle progenitors, and satellite cells), gene editing, exosome-mediated delivery, and biomaterial scaffolds. Emerging evidence highlights the therapeutic potential of engineered exosomes, pro-regenerative cytokines, and biomimetic scaffolds in enhancing angiogenesis, myogenesis, and immune modulation. In parallel, advances in multi-omics and artificial intelligence are accelerating the identification of key molecular targets and the development of personalized interventions. Combination therapies that integrate cellular, molecular, and structural approaches demonstrate synergistic benefits for improving outcomes. This review summarizes current knowledge of the molecular mechanisms underlying muscle degeneration and discusses emerging therapeutic strategies that hold promise for effective muscle regeneration.
Grhl3 coordinates epithelial gene activation and epigenetic remodeling in fibroblasts.
Yaprak İ, Alotaibi H
Exp Cell Res · 2026 Apr · PMID 41759702 · Publisher ↗
The mesenchymal-to-epithelial transition (MET) is a critical and stepwise process in cellular reprogramming and development. Grhl3 has been implicated in MET, but its capacity to initiate epithelial programs in non-epith...
The mesenchymal-to-epithelial transition (MET) is a critical and stepwise process in cellular reprogramming and development. Grhl3 has been implicated in MET, but its capacity to initiate epithelial programs in non-epithelial cells remains incompletely defined. Here, we demonstrate that Grhl3 overexpression in MEFs induces a transcriptional shift consistent with early MET, characterized by activation of epithelial genes and suppression of mesenchymal features. This response is accompanied by chromatin changes indicative of gene activation at epithelial loci and is reinforced through cooperative interactions with other MET-associated transcription factors. Grhl3 is associated with locus-specific changes in DNA methylation and with regulatory engagement at genes involved in epigenetic maintenance. Together, these findings position Grhl3 as a central coordinator of epithelial gene activation and epigenetic remodeling in a non-epithelial context, supporting its role in initiating early, transcriptionally and epigenetically primed MET states.
From code to cancer: CircRNAs and lncRNAs regulate kinesin functions in tumorigenesis.
Alsa'd AA, Al-Hasnaawei S, Renuka Jyothi S … +4 more , Nayak PP, Bethanney Janney J, Arora V, Sinha A
Exp Cell Res · 2026 Apr · PMID 41740825 · Publisher ↗
There has been a paradigm shift in the pathogenesis mechanisms of cancer over the past few decades in oncology, whereby the regulators of tumorigenesis are non-coding RNAs (ncRNAs). Circular RNAs (circRNAs) and long non-...
There has been a paradigm shift in the pathogenesis mechanisms of cancer over the past few decades in oncology, whereby the regulators of tumorigenesis are non-coding RNAs (ncRNAs). Circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) have also recently been of great interest due to their roles as regulatory molecules in pathological processes, including cancer. These regulatory molecules operate partially by interfering with kinesin superfamily proteins (KIFs)-cellular molecular motors implicated in the transport phenomena within a cell and related processes, including post-mitotic and basic cell functions. Cumulative evidence shows that ncRNA-KIF networks operate through independent mechanistic pathways. In most cases, circRNAs function as competitive endogenous RNAs by sequestering microRNAs and modulating the indirect pathway of KIF expression. lnRNAs can bind protein or mRNA of KIF directly and modify its function or stability. Briefly, they all share a broad range of cancer hallmarks such as heightened proliferative signaling pathways, drug resistance, and invasion and metastasis. Several ncRNA-KIF axes are tissue-specific in the three cancers, namely glioblastoma, breast cancer, and colorectal carcinoma, and thus are also potential therapeutic targets, along with biomarkers. The clinical relevance of this finding is that strong ncRNA-KIF signatures would likely allow for the early detection of cancer with a favorable prognosis; such interactions would unveil novel therapies, particularly in therapy-refractory tumors. For example, inhibiting oncogenic ncRNA-KIF networks or restoring tumor-suppressive ones would be related to all existing methods. With advancing science, a progressively more evolved view of such regulatory networks will reveal increasingly complex layers in cancer biology and identify novel targets for RNA-based therapies. Such advances in new knowledge underscore the importance of extending current research into ncRNA-KIF interactions and their translational relevance to precision oncology.
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