Experimental Cell Research[JOURNAL]
Sun
200 papers
Atomic force microscopy imaging of RBL-2H3 cell degranulation.
Li J, Hu J, Chen Y … +4 more , Wang B, Crabbe MJC, Wang Z, Ju T
Exp Cell Res · 2026 Jul · PMID 42097440 · Publisher ↗
Understanding the biophysical mechanisms of degranulation is crucial for managing allergic diseases, yet the spatiotemporal coordination of membrane and cytoskeletal dynamics during these reactions remains incompletely u...
Understanding the biophysical mechanisms of degranulation is crucial for managing allergic diseases, yet the spatiotemporal coordination of membrane and cytoskeletal dynamics during these reactions remains incompletely understood. In this study, we utilized Atomic Force Microscopy (AFM) to conduct a time-resolved investigation of RBL-2H3 cells during anti-DNP IgE-induced activation. By systematically mapping the cell surface, we quantified phase-specific changes in morphology, surface adhesion, and cortical stiffness (Young's modulus). Our results reveal a striking temporal asynchronicity, with cell height and surface adhesion peaking at 8 h, reflecting receptor-driven membrane ruffling and sensitization. In contrast, the Young's modulus reached its maximum at 12 h, indicating a delayed mechanical reinforcement driven by profound cytoskeletal rearrangement for active granule transport. Furthermore, we characterized the collapsed-sphere ultrastructure of secreted extracellular vesicles (EVs). These findings successfully decouple the initial membrane sensitization from the subsequent intracellular execution phase, identifying novel nanomechanical biomarkers to understand vesicle-mediated communication and to guide the design of stage-specific therapeutic interventions.
Role of paraptosis in cancer: Molecular mechanisms and therapeutic potentials.
Li YG, Hao MY, Li HJ … +5 more , Han HS, Laila UE, Si WR, Jiang QY, Wu DD
Exp Cell Res · 2026 Jul · PMID 42066942 · Publisher ↗
Paraptosis represents a mode of cell death, which is separate from classical apoptosis. Classical apoptotic pathways are caspase-dependent, accompanied by cell shrinkage, chromatin condensation, and apoptotic body format...
Paraptosis represents a mode of cell death, which is separate from classical apoptosis. Classical apoptotic pathways are caspase-dependent, accompanied by cell shrinkage, chromatin condensation, and apoptotic body formation. In contrast, paraptosis is characterized by cytoplasmic vacuolization without typical apoptotic nuclear alterations, and its signaling operates independently of the caspase system. Unlike apoptosis, paraptosis primarily depends on the mitogen-activated protein kinase (MAPK) signaling pathway for its mediation, highlighting its unique regulatory framework separate from classical apoptotic pathways. Since it does not overlap with apoptotic resistance mechanisms, inducing paraptosis holds great potential to overcome resistance to conventional chemotherapy and radiotherapy. Therefore, inducing paraptosis in cancer cells has crucial potential value for current cancer treatment. This article thoroughly explores the regulatory mechanisms of paraptosis and synthesizes its dual functions in the progression of cancer cells. Additionally, we discuss in detail cancer treatment strategies based on targeting paraptosis and analyze the feasibility and potential advantages of combining paraptosis with other cell death forms and various therapeutic methods to enhance cancer treatment efficacy.
CircRNA_38959 protects liver cells from intermittent hypoxia-triggered injury and suppresses ferroptosis by interacting with IGF2BP3.
Li C, Lin J, Guo Y … +2 more , Fang T, Liang Y
Exp Cell Res · 2026 Jul · PMID 42066941 · Publisher ↗
Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is closely associated with liver injury and ferroptosis. However, the molecular mechanisms underlying IH-induced liver damage remain largely unexplo...
Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is closely associated with liver injury and ferroptosis. However, the molecular mechanisms underlying IH-induced liver damage remain largely unexplored. Here, we identify circ_38959 as a novel liver-protective circular RNA that mitigates IH-induced injury and ferroptosis. Circ_38959 overexpression in AML-12 hepatocytes significantly rescued cell viability, reduced apoptosis, and suppressed ferroptosis under IH conditions. Mechanistically, RNA immunoprecipitation uncovered that IGF2BP3 functions as a key interacting protein of circ_38959. Knocking down circ_38959 can down-regulate the protein expressions of IGF2BP3, c-Myc and c-Met. Functional studies revealed that IGF2BP3 deficiency abrogated the protective effects of circ_38959, confirming its essential role in liver protection and ferroptosis suppression. In an IH mouse model, AAV-mediated overexpression of circ_38959 effectively rescued liver function, and suppressed ferroptosis. Collectively, our study unveils a circ_38959-IGF2BP3 interaction that protects against IH-induced liver damage, highlighting circ_38959 as a potential therapeutic target for liver injury associated with OSA.
ALPK1 promotes cardiomyocyte hypertrophy by activating NF-κB/NLRP3 inflammasome-mediated pyroptosis.
Zhuang X, Han S, Dong Z … +5 more , Pei W, Li J, Sun H, Liu M, Lu J
Exp Cell Res · 2026 Jul · PMID 42061549 · Publisher ↗
BACKGROUND: Cardiac hypertrophy is a leading risk factor for cardiovascular morbidity and mortality. Alpha-protein kinase 1 (ALPK1) is a novel essential player in innate immunity and inflammation. Therapeutic agents targ...
BACKGROUND: Cardiac hypertrophy is a leading risk factor for cardiovascular morbidity and mortality. Alpha-protein kinase 1 (ALPK1) is a novel essential player in innate immunity and inflammation. Therapeutic agents targeting ALPK1 have successively entered clinical trials and become research hotspots. However, the role of ALPK1 on cardiac hypertrophy remains unknown. METHODS: In the present study, transverse aortic constriction (TAC) was used to establish in vivo models of cardiac hypertrophy. Neonatal mouse cardiomyocytes (NMCMs) and AC16 human cardiomyocytes treated with angiotensin Ⅱ (Ang Ⅱ) were performed to mimic in vitro models of cardiac hypertrophy. ALPK1 gene expression was knocked down by small interfering RNAs (siRNAs) and overexpressed by transfection with plasmid, respectively. RESULTS: ALPK1 was significantly upregulated in cardiac hypertrophy. ALPK1 knockdown effectively suppressed Ang Ⅱ-induced upregulated hypertrophic markers, enlarged cell surface area, decreased cell viability, increased lactate dehydrogenase release, enhanced caspase-1 activity, elevated positive pyroptotic cells, as well as the upregulation of p-NF-κB p65, NLRP3 inflammasome and pyroptosis markers in both NMCMs and AC16 cells. ALPK1 knockdown markedly suppressed the increased secretion of IL-1β and IL-18 induced by Ang Ⅱ in NMCMs. Consistently, ALPK1 over-expression significantly increased the expression of hypertrophic markers, enhanced the cell surface area, elevated the number of pyroptotic cells, upregulated the protein expression of NLRP3 inflammasome and pyroptosis markers, increased the secretion of IL-1β and IL-18, which were successfully reversed by the addition of MCC950, a selective NLRP3 inflammasome inhibitor. However, MCC950 treatment showed no effect on the upregulation of ALPK1 and p-NF-κB p65 induced by ALPK1 over-expression. CONCLUSION: ALPK1 promotes cardiomyocyte hypertrophy by activating NF-κB/NLRP3 inflammasome-mediated pyroptosis, providing new potential applications for agents targeting ALPK1 in the immunotherapy of cardiac hypertrophy.
The ATF4/PSAT1/JNK signaling axis suppresses ferroptosis to drive venetoclax resistance in AML.
Zhu X, Huang W, Zhang M … +2 more , Tao Y, Zhang H
Exp Cell Res · 2026 Jul · PMID 42044713 · Publisher ↗
Metabolic reprogramming has emerged as a key driver of therapy resistance in acute myeloid leukemia (AML). Here, we identify phosphoserine aminotransferase 1 (PSAT1) as a critical metabolic determinant of venetoclax (VEN...
Metabolic reprogramming has emerged as a key driver of therapy resistance in acute myeloid leukemia (AML). Here, we identify phosphoserine aminotransferase 1 (PSAT1) as a critical metabolic determinant of venetoclax (VEN) resistance through the suppression of ferroptosis. PSAT1 was consistently upregulated in VEN-resistant cell lines and relapsed patient samples. Mechanistically, the transcription factor ATF4 directly bound the PSAT1 promoter, enhancing its expression and subsequently promoting glutathione synthesis, depleting the labile iron pool, and attenuating lipid peroxidation. Concurrently, PSAT1 functioned to restrain JNK/c-Jun signaling. Knockdown of PSAT1 restored VEN sensitivity by triggering ferroptosis and modulating the expression of BCL-2 and GPX4. Clinically, elevated PSAT1 expression predicted poor patient survival. Our findings unveil the ATF4/PSAT1/JNK axis as a master regulator of ferroptosis in AML, revealing a druggable pathway to overcome VEN resistance.
Reinventing miRNA cancer therapy through immunomodulation and AI.
Zhou Y, Liu Y, Lv Y … +3 more , Fang Y, Xu C, Wu H
Exp Cell Res · 2026 Jul · PMID 42044712 · Publisher ↗
Despite the rational therapeutic premise of microRNA (miRNA) replacement or inhibition for cancer treatment, its clinical translation remains significantly constrained. Major challenges span from inherent molecular insta...
Despite the rational therapeutic premise of microRNA (miRNA) replacement or inhibition for cancer treatment, its clinical translation remains significantly constrained. Major challenges span from inherent molecular instability and off-target effects to substantial delivery hurdles. This persistent translational impasse continues despite continuous advancements in oligonucleotide chemistry and delivery platform engineering, underscoring an urgent need to re-evaluate the current developmental pathway. This review systematically delineates the significant therapeutic potential of miRNAs as pivotal gene regulators in oncology, alongside the current challenges in clinical translation posed by their unique biological complexity and delivery hurdles. Considering that, we highlight two pivotal frontiers poised to reshape the field: first, the strategic integration of miRNA therapeutics with modern immunotherapies to enhance anti-tumor efficacy; second, the application of artificial intelligence (AI) to deconvolute miRNA biology and accelerate rational drug design. An objective appraisal of persistent translational barriers, including robust in vivo target validation, long-term safety, and the interpretability of complex computational models, is also provided. We conclude that realizing the full clinical potential of miRNA therapy will necessitate a convergent approach, integrating intelligent delivery technologies, multi-omics-guided precision, and deep interdisciplinary collaboration.
Matrix stiffness disrupts tight junction integrity in retinal pigment epithelial cells via YAP1-mediated autophagy suppression.
Wang S, Zhang Y, Yang N … +2 more , Cui J, Zhao J
Exp Cell Res · 2026 Jul · PMID 42044711 · Publisher ↗
BACKGROUND: The extracellular matrix (ECM) of retinal pigment epithelial (RPE) cells undergoes progressive stiffening during aging and under pathological conditions. However, how such mechanical effects affect RPE cell f...
BACKGROUND: The extracellular matrix (ECM) of retinal pigment epithelial (RPE) cells undergoes progressive stiffening during aging and under pathological conditions. However, how such mechanical effects affect RPE cell function remains incompletely understood. This study aims to investigate the effect of stiffness of ECM on autophagy in RPE cells and its regulatory role on tight junctions. METHODS: ARPE-19 cells were cultured on polyacrylamide hydrogel substrates with low (5 kPa) and high (40 kPa) stiffness. The expression and subcellular localization of tight junction proteins and autophagy-related markers were assessed by Western blotting, quantitative PCR, and immunofluorescence staining. Autophagy was pharmacologically modulated using the autophagy activator rapamycin and the inhibitor chloroquine to evaluate the effects of autophagy on tight junction integrity. In addition, Yes-associated protein 1(YAP1) was knocked down using shRNA to investigate its role in ECM stiffness-mediated regulation of autophagy and tight junction alterations. RESULTS: Polyacrylamide hydrogel substrates with low stiffness (5 kPa) and high stiffness (40 kPa) had no significant effect on the growth or proliferation of ARPE-19 cells. High-stiffness substrates markedly suppressed autophagic activity in ARPE-19 cells and downregulated the expression of tight junction proteins zonula occludens-1 (ZO-1), occludin, and claudin-19, resulting in disruption of tight junction integrity. Pharmacological inhibition of autophagy further exacerbated tight junction damage, whereas autophagy activation partially reversed the tight junction impairment induced by high matrix stiffness. Moreover, knockdown of YAP1 substantially attenuated the inhibitory effects of high stiffness on autophagy and tight junction protein expression. CONCLUSION: Increased ECM stiffness impairs tight junction integrity in ARPE-19 cells through a YAP1-mediated suppression of autophagy.
The role of disease-modifying anti-rheumatic drugs (DMARDs) in cardiovascular risk management induced by rheumatoid arthritis.
Wang Y, Zhang N, He CX … +11 more , Zhou X, Fu J, Li PQ, Li P, Zhao XX, Gao YT, Chu HQ, Zhao D, Qin W, Chen ZS, Cao HL
Exp Cell Res · 2026 Jun · PMID 42034307 · Publisher ↗
Rheumatoid arthritis (RA) is a prevalent autoimmune disease affecting approximately 1% of the global population, which significantly increases the risks of cardiovascular disease (CVD). RA-associated cardiovascular risks...
Rheumatoid arthritis (RA) is a prevalent autoimmune disease affecting approximately 1% of the global population, which significantly increases the risks of cardiovascular disease (CVD). RA-associated cardiovascular risks, such as pericarditis, myocarditis, heart failure, myocardial infarction, arrhythmias, atherosclerosis, and endothelial dysfunction, are major contributors to mortality in RA patients. These risks are driven by a complex interplay of chronic immune-inflammatory activation, metabolic dysregulation, genetic factors, and the adverse effects of long-term drug therapy. Despite advances in understanding the mechanisms of CVD in RA and their interplay with traditional risk factors, optimal approaches for risk management in this patient population are not yet well-defined. Cardiovascular risk assessment in RA patients requires regular monitoring of traditional risk factors and disease activity, supplemented by emerging biomarkers and imaging techniques. Disease-modifying anti-rheumatic drugs (DMARDs) are central to managing both RA and cardiovascular risks. The potential role of cell therapy in cardiovascular risk management induced by RA also is discussed. Despite progress in understanding RA-related cardiovascular risks, challenges remain in predicting patient outcomes. Future research should focus on identifying novel biomarkers for early detection, developing personalized management strategies, and evaluating the long-term effects of immunomodulatory therapies on cardiovascular risks.
MDK promotes the mast cell activation and pancreatic fibrosis in mice with chronic pancreatitis via MDK-NCL signaling pathway.
Xiong J, Song J, Jiang X … +2 more , Huang Z, Zhang Y
Exp Cell Res · 2026 Jul · PMID 42031197 · Publisher ↗
Chronic pancreatitis (CP) is characterized by persistent inflammation and fibrosis in the pancreas, but its exact pathogenesis remains unclear. To investigate the underlying mechanisms, human CP single-cell RNA sequencin...
Chronic pancreatitis (CP) is characterized by persistent inflammation and fibrosis in the pancreas, but its exact pathogenesis remains unclear. To investigate the underlying mechanisms, human CP single-cell RNA sequencing (scRNA-seq) data (GSE208536) were analyzed for clustering and cell communication, while a dibutyltin dichloride (DBTC)-induced CP mouse model was established. Flow cytometry was used to analyze cell phenotypes and sort cells. Bioinformatics analysis revealed that pancreatic stellate cells (PSCs) and mast cells play a pivotal role in CP progression, with a significant enrichment in the midkine (MDK)-nucleolin (NCL) ligand-receptor pair. In CP mice, we confirmed concurrent upregulation of fibrotic markers (α-SMA, Collagen I, FN1) and mast cell mediators (HIS, MCT, NGF, C-kit, IL-18), alongside elevated MDK/NCL expression and infiltration of both PSCs and mast cells. Functional validation showed that MDK knockdown in PSCs reduced activation and fibrosis, and suppressed proliferation and degranulation in mast cells. These effects were reversed by recombinant MDK. Additionally, NCL neutralization blocked mast cell activation in wild-type co-cultures. Crucially, in vivo knockdown of MDK or NCL reduced cell infiltration and activation, thus alleviating pancreatic damage and fibrosis. In conclusion, the MDK-NCL axis contributes to interactions between PSCs and mast cells, thereby exacerbating fibrosis and inflammation in CP. These findings provide a mechanistic insight into CP pathogenesis and identify the MDK-NCL axis as a candidate for future functional studies.
Chemogenetic screen identifies EphA2 as a synthetic lethal vulnerability in MYC-driven triple-negative breast cancer.
Ye M, Wang Z, Wang Y … +2 more , Sun Z, Luan X
Exp Cell Res · 2026 Jul · PMID 42031196 · Publisher ↗
The MYC oncoprotein is a key driver of various cancers and is particularly relevant in triple-negative breast cancer (TNBC), where its dysregulated activation promotes aggressive tumor growth, metastasis, and resistance...
The MYC oncoprotein is a key driver of various cancers and is particularly relevant in triple-negative breast cancer (TNBC), where its dysregulated activation promotes aggressive tumor growth, metastasis, and resistance to treatment. Despite its central role in cancer development, directly targeting MYC proves challenging due to its disordered structure and lack of druggable pockets. Synthetic lethality, a strategy that exploits secondary vulnerabilities in MYC-driven cancer cells, offers a promising therapeutic approach. In this study, we establish a chemogenetic screening platform to identify compounds that selectively target MYC-driven cancer cells. We screen a library of approximately 600 kinase inhibitors and identify ALW-II-41-27, an EphA2 inhibitor, as a top hit. ALW-II-41-27 demonstrates strong MYC-selective cytotoxicity and induces apoptosis in MYC-activated cells through the intrinsic apoptotic pathway. Importantly, this apoptotic response is independent of p53 status, which is frequently inactivated by loss-of-function mutations in MYC-driven cancers. In vivo, ALW-II-41-27 effectively inhibits tumor growth in MDA-MB-231 and MDA-MB-468 TNBC xenografts without apparent toxicity. These findings highlight EPHA2 as a novel synthetic lethal partner of MYC and suggest that targeting EPHA2 could offer a promising therapeutic strategy for MYC-driven TNBC.
The combinations of histone lysine demethylase inhibitors with panobinostat exert enhanced effects against head and neck cancer cells.
Dorna D, Kleszcz R, Drabarz K … +3 more , Kubiak M, Stefanska B, Paluszczak J
Exp Cell Res · 2026 Jul · PMID 42019757 · Publisher ↗
The effectiveness of treatment of head and neck squamous cell carcinomas (HNSCC) is still unsatisfactory, and novel therapeutics could improve outcomes. Histone deacetylases (HDAC) and histone lysine demethylases (KDMs)...
The effectiveness of treatment of head and neck squamous cell carcinomas (HNSCC) is still unsatisfactory, and novel therapeutics could improve outcomes. Histone deacetylases (HDAC) and histone lysine demethylases (KDMs) emerged as important molecular targets in HNSCC. Moreover, joint inhibition of epigenetic targets may be therapeutically advantageous. Thus, the aim of this project was to evaluate the effects of combinations of panobinostat, a pan-HDAC inhibitor, with KDM4-6 inhibitors (KDMi), ML324, GSK-J4, and JIB-04. Experiments were performed in FaDu and SCC-152 cell lines. Resazurin and clonogenic assays were used to evaluate the cell viability and clonogenic potential, respectively. Apoptosis was assessed by flow cytometry after Annexin V staining. Flow-cytometric detection of γH2A.X was applied for DNA damage evaluation. Gene expression was quantified by qPCR. KDM proteins occupancy at gene promoters was measured by quantitative chromatin immunoprecipitation. KDMi enhanced the anticancer effects of panobinostat in HNSCC cell lines. The combinations of panobinostat with ML324 and JIB-04 synergistically reduced cell viability in FaDu and SCC-152 cells, and increased apoptosis induction in SCC-152 cells. These effects could be attributed to the modulation of BIRC5 and CDKN2A expression, and enhanced accumulation of DNA double-strand breaks following combinatorial treatments in FaDu cells. Decreased expression of stemness-related genes upon KDMi treatment in FaDu cells was associated with decreased binding of KDM4A and/or KDM6B at SOX2 and POU5F1 gene promoters. The suppression of stemness-associated phenotype, and the concurrent promotion of apoptosis by the studied combinations of chemicals, suggest their potential as a novel therapeutic strategy in HNSCC.
GFPT1 facilitates immune escape in lung adenocarcinoma by promoting the O-GlcNAcylation of MYC and regulating PD-L1.
Xu W, Hao H, Chi F … +5 more , Xia C, Zheng S, Liu W, Cai T, Liu X
Exp Cell Res · 2026 Jun · PMID 41999836 · Publisher ↗
Lung adenocarcinoma (LUAD) is a leading cause of cancer-related death worldwide. Immunotherapies that overcome tumor immune evasion have emerged as promising strategies. GFPT1, the rate-limiting enzyme of the hexosamine...
Lung adenocarcinoma (LUAD) is a leading cause of cancer-related death worldwide. Immunotherapies that overcome tumor immune evasion have emerged as promising strategies. GFPT1, the rate-limiting enzyme of the hexosamine biosynthetic pathway, is commonly dysregulated in malignancies. The aim of this work is to investigate the functional significance and molecular basis of GFPT1 in immune escape of LUAD. GFPT1 expression was evaluated through integrated bioinformatic analysis and validation in clinical specimens. Functional assays were employed to assess tumor cell-mediated immune evasion. Mmechanistic investigations were supported by molecular assays and in vivo models. We demonstrated that elevated GFPT1 expression in LUAD promotes immune escape of tumor cells. Mechanically, GFPT1 stabilized the expression of MYC by O-GlcNAcylation of MYC, thereby contributing to LUAD progression. Overall, this study revealed the promoting effect of GFPT1 on the immune escape of LUAD, which provided new therapeutic targets for the immunotherapy of LUAD.
Arginase 2 regulates cholesterol biosynthesis in endothelial cells.
Zhang Y, Yu M, Huang J
Exp Cell Res · 2026 Jun · PMID 41997283 · Publisher ↗
BACKGROUND: Arginase 2 (Arg 2) is a mitochondrial enzyme that hydrolyzes L-arginine to L-ornithine and urea, influencing endothelial nitric oxide (NO) bioavailability and vascular function. Although Arg 2 is implicated i...
BACKGROUND: Arginase 2 (Arg 2) is a mitochondrial enzyme that hydrolyzes L-arginine to L-ornithine and urea, influencing endothelial nitric oxide (NO) bioavailability and vascular function. Although Arg 2 is implicated in endothelial dysfunction under hypercholesterolemic and oxidative stress conditions, its potential role in endothelial cholesterol metabolism remains unknown. METHODS: Arg 2 was deleted in immortalized human umbilical vein endothelial cells (HUVECs) using CRISPR/Cas9, followed by transcriptomic analyses. Differential gene expression was validated by quantitative RT-PCR and immunoblotting. Overexpression of wild-type Arg 2 and the catalytically inactive Arg 2 (H160F) mutant was achieved using recombinant lentiviral transduction. Arginase activity was quantified by measuring urea production using a colorimetric assay. Cholesterol intermediates were quantified by LC-MS. RESULTS: RNA sequencing revealed that Arg 2 deletion markedly downregulated genes involved in the mevalonate and steroid biosynthesis pathways, including HMGCS1, FDFT1, FDPS, SQLE, and DHCR7. These transcriptional changes were accompanied by reduced protein levels of key cholesterol biosynthetic enzymes and decreased cellular concentrations of sterols, lanosterol, desmosterol, and cholesterol. Conversely, either overexpression of wild-type Arg 2 or the catalytically inactive Arg 2 (H160F) mutant enhanced the expression of these enzymes. CONCLUSIONS: These findings identify a previously unrecognized role of Arg 2 in promoting endothelial cholesterol biosynthesis. Beyond competing with endothelial NO synthase for L-arginine, Arg 2 may regulate vascular homeostasis through modulation the mevalonate pathway, independent of its enzymatic activity. This dual function may link amino acid and lipid metabolism in the endothelium and suggests new mechanisms by which Arg 2 contributes to endothelial dysfunction and atherosclerotic progression.
RET inhibition by selpercatinib suppresses TGF-β1-induced epithelial-mesenchymal transition in retinal pigment epithelium.
Chen M, Zhao R, Chen X … +2 more , Xu L, Hu C
Exp Cell Res · 2026 Jun · PMID 41997282 · Publisher ↗
PURPOSE: The transforming growth factor-β (TGF-β) pathway is a master regulator of epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells, a key process in fibrotic ocular diseases. However, ke...
PURPOSE: The transforming growth factor-β (TGF-β) pathway is a master regulator of epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells, a key process in fibrotic ocular diseases. However, key modulators fine-tuning this pathway in RPE are incompletely characterized. This study investigates the role of the receptor tyrosine kinase RET in TGF-β1-induced RPE-EMT. METHODS: The role of RET was assessed in vitro using the clinically approved RET inhibitor, Selpercatinib, in RPE cells stimulated with TGF-β1. Outcomes included EMT markers, migration, proliferation, and transcriptional reprogramming. Key downstream signaling effectors Smad3 and ERK were analyzed. In vivo validation was performed in mouse models of TGF-β1-induced EMT and sodium iodate (NaIO)-induced RPE injury. RESULTS: Pharmacological inhibition of RET with Selpercatinib effectively suppressed TGF-β1-induced EMT, migration, proliferation, and associated transcriptional reprogramming in RPE cells. Mechanistically, RET kinase activity was required for the TGF-β1-induced activation of Smad3 and ERK. In mouse models, Selpercatinib treatment attenuated RPE-EMT and preserved retinal structure. CONCLUSIONS: Our findings establish RET as a critical modulator in the TGF-β signaling pathway in RPE cells and highlight the therapeutic potential of repurposing RET inhibitors for the treatment of fibrotic retinal diseases.
Glutathione-conjugated gold nanoparticles mitigate amyloid-beta-induced neuroinflammation and tauopathy through inhibition of NF-κB, the NLRP3 inflammasome axis in 3D human neural stem cell models.
Yang YP, Nicol CJB, Yen C … +1 more , Chiang MC
Exp Cell Res · 2026 Jun · PMID 41997281 · Publisher ↗
Neuroinflammation and tauopathy are central pathological features of Alzheimer's disease (AD), often exacerbated by amyloid-β (Aβ) accumulation. This study evaluated the therapeutic potential of glutathione-conjugated go...
Neuroinflammation and tauopathy are central pathological features of Alzheimer's disease (AD), often exacerbated by amyloid-β (Aβ) accumulation. This study evaluated the therapeutic potential of glutathione-conjugated gold nanoparticles (GSH-AuNPs) in mitigating Aβ-induced cytotoxicity and inflammation using a physiologically relevant 3D human neural stem cell (hNSCs) model cultured within a gelatin scaffold. This 3D system provided a tissue-like microenvironment to closely mimic in vivo conditions. GSH-AuNP treatment significantly rescued Aβ-induced loss of cell viability and suppressed tumor necrosis factor-α (TNF-α) secretion. At the molecular level, GSH-AuNPs downregulated the expression of key inflammatory mediators, including IKKα, IKKβ, and NF-κB (p65), and inhibited nuclear translocation of p65. Additionally, GSH-AuNPs attenuated the expression of proinflammatory enzymes iNOS and COX-2 and suppressed activation of the NLRP3 inflammasome, as evidenced by reduced levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18. Proteostasis was improved by restoring chymotrypsin-like proteasome activity and reducing phosphorylated tau accumulation. Furthermore, GSH-AuNPs enhanced cellular resilience by upregulating heat shock factor 1 (HSF1) and normalizing the expression of key molecular chaperones HSP27, HSP70, and HSP90. Our findings highlight the multifaceted protective effects of GSH-AuNPs in counteracting Aβ-induced neuroinflammation and tauopathy. These results support the potential application of GSH-AuNPs as a nanomedicine-based therapeutic strategy for AD.
The Caenorhabditis elegans mitochondrial electron transport chain: its role in adaptation, longevity, and biotechnology.
Hernández-Cruz EY, Uribe-Carvajal S
Exp Cell Res · 2026 Jun · PMID 41985607 · Publisher ↗
In Caenorhabditis elegans (C. elegans) the mitochondrial electron transport chain (ETC) exhibits remarkable functional plasticity. This review summarizes the composition, regulation, and adaptive roles of complexes I-V....
In Caenorhabditis elegans (C. elegans) the mitochondrial electron transport chain (ETC) exhibits remarkable functional plasticity. This review summarizes the composition, regulation, and adaptive roles of complexes I-V. Depending on oxygen availability, the ETC uses either ubiquinone (UQ) or rhodoquinone (RQ), an ancestral strategy for hypoxia or high hydrogen sulfide (HS) conditions. Mild ETC impairments can extend lifespan through redox signaling, mitohormesis, and activation of the mitochondrial unfolded protein response. These processes likely represent conserved mechanisms of bioenergetic adaptation and longevity. Moreover, C. elegans serves as a translational model for human mitochondrial diseases and for screening mitochondrial or antiparasitic compounds.
Molecular mechanisms and genetic factors in the development and progression of urinary system disorders.
Chen K, Wu L, Feng D
Exp Cell Res · 2026 Jun · PMID 41980620 · Publisher ↗
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ELFN2 inhibits YAP-driven lymph node metastasis in gastric cancer by blocking PP1A-mediated dephosphorylation.
Ling R, Yang H, Zhang G … +9 more , Chen J, Ye Z, Gou L, Lei X, Yang Q, Peng Y, Ye G, Li G, Chen H
Exp Cell Res · 2026 Jun · PMID 41967793 · Publisher ↗
Lymph node metastasis (LNM) is the most frequent metastatic pathway in gastric cancer (GC) and a major determinant of poor prognosis, but the underlying molecular mechanisms remain poorly defined. In this study, we inves...
Lymph node metastasis (LNM) is the most frequent metastatic pathway in gastric cancer (GC) and a major determinant of poor prognosis, but the underlying molecular mechanisms remain poorly defined. In this study, we investigated the role of extracellular leucine-rich repeat and fibronectin type III domain-containing protein 2 (ELFN2) in LNM and its therapeutic potential in GC. ELFN2 expression was examined in clinical GC tissues and found to be significantly downregulated in cases with LNM, with low ELFN2 levels correlating with unfavorable patient survival. Mechanistic studies demonstrated that ELFN2 interacts directly with the catalytic subunit alpha of protein phosphatase-1 (PP1A), thereby inhibiting YAP dephosphorylation at Ser127. This regulation promotes YAP nuclear export and functional inactivation. Pharmacological inhibition of PP1A abrogated ELFN2-induced YAP inactivation, confirming the requirement of PP1A in this process. To further validate the biological significance of ELFN2, we established in vivo models of LNM and peritoneal carcinomatosis, which consistently showed that ELFN2 suppresses metastatic dissemination. Together, our results reveal a novel ELFN2/PP1A/YAP signaling axis that plays a critical role in controlling LNM in GC. Importantly, these findings not only provide new insights into the molecular mechanisms governing GC metastasis but also highlight ELFN2 as a promising biomarker and potential therapeutic target for the management of GC patients at high risk of LNM.
THOC6 deficiency leads to cardiomyopathy by reducing myocardial contractile proteins in cardiomyocytes.
Yuan W, Jiang Z, Li F … +3 more , Chen H, Zhang X, Fan X
Exp Cell Res · 2026 Jun · PMID 41967792 · Publisher ↗
BACKGROUND: The THOC6 protein is an essential part of the THO complex. Biallelic loss-of-function variants in the THOC6 gene are linked to Beaulieu-Boycott-Innes syndrome (BBIS; OMIM #613680). Although research predomina...
BACKGROUND: The THOC6 protein is an essential part of the THO complex. Biallelic loss-of-function variants in the THOC6 gene are linked to Beaulieu-Boycott-Innes syndrome (BBIS; OMIM #613680). Although research predominantly focuses on THOC6's involvement in neurodevelopmental disorders, approximately 80% of BBIS patients present with cardiac anomalies, including structural heart disease, cardiomyopathy, and arrhythmia. Despite this, the connection between THOC6 expression and cardiac development remains underexplored. This study firstly investigates THOC6's role in heart development. METHODS AND RESULTS: This study we firstly utilized CRISPR/Cas9 to knock out THOC6 in H9C2 cardiomyocytes, revealing a reduction in cell proliferation and an increase in apoptosis. With RNA sequencing (RNA-seq) analysis we found abundant gene changes after THOC6 knockout (KO) in H9C2, which associated with hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and dilated cardiomyopathy. Protein-protein interaction analysis and experimental validation indicated that THOC6 regulates the expression of type I collagen (COL1A1, COL1A2) and cytoskeletal protein (Cardiac α actin 1) in cardiomyocytes. Subsequently, we generated a THOC6 knockout cell lines in human induced pluripotent stem cells (hiPSCs) derived from a healthy individual using CRISPR/Cas9 technology. THOC6 knockout (KO) in hiPSCs-derived cardiomyocytes (hiPSC-CMs) led to the early manifestation of hypertrophic cardiomyopathy and dilated cardiomyopathy phenotypic characteristics, including disrupted sarcomeric organization. Notably, THOC6 KO hiPSC-CMs demonstrated a significant decreased in COL1A2 and β-tubulin expression levels. CONCLUSION: THOC6 may influence cardiac development by regulating myocardial contractile proteins, primarily type I collagen, cardiac α actin 1 and β-tubulin.
Epigenetic and post-transcriptional integration of lncRNAs and EZH2 in GI tumorigenesis.
Ibrahim Mohammad S, B Gajjar T, R Baig M … +7 more , Vasudevan A, Hanumanthayya M, Prasannakumar M, Kumar Shukla S, Kumar Tailor N, Hussien S, Abdelgawwad El-Sehrawy AAM
Exp Cell Res · 2026 Jun · PMID 41967791 · Publisher ↗
Gastrointestinal (GI) cancers, more broadly, colorectal, gastric, pancreatic, and esophageal malignancies, remain major contributors to global cancer mortality, driven by late diagnosis, metastasis, and resistance to the...
Gastrointestinal (GI) cancers, more broadly, colorectal, gastric, pancreatic, and esophageal malignancies, remain major contributors to global cancer mortality, driven by late diagnosis, metastasis, and resistance to therapy. Increasing evidence highlights the enhancer of zeste homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), as a central epigenetic driver of GI tumorigenesis through deposition of H3K27me3 and silencing of tumour-suppressor genes. However, the oncogenic functions of EZH2 are not autonomous; long non-coding RNAs (lncRNAs) critically shape its locus specificity, chromatin recruitment, stability, and integration into broader transcriptional programs. Numerous lncRNAs in GI cancers, such as LINC00337, LINC00673, ZFAS1, MSTO2P, and HOXA-AS2, recruit EZH2 to repress key regulators of the cell cycle and differentiation. Other lncRNAs act through ceRNA mechanisms to de-repress EZH2 expression, or engage EZH2 within oncogenic signalling pathways including AKT, STAT3, Notch, and Wnt/β-catenin. These interactions contribute to malignant proliferation, invasion, metastasis, cancer stemness, and therapeutic resistance. Despite intense investigation, mechanistic ambiguity remains due to limitations in distinguishing direct EZH2 recruitment from correlative chromatin association, and in validating ceRNA activity within physiologic stoichiometric constraints. Nevertheless, the lncRNA-EZH2 axis presents a promising therapeutic avenue, with RNA-based strategies offering the potential to disrupt pathological lncRNA-EZH2 assemblies with greater precision than catalytic EZH2 inhibitors alone. This review synthesizes current mechanistic and functional insights into lncRNA-EZH2 regulation in GI cancers, organizing these interactions into key biological modules and highlighting emerging opportunities for diagnostic and therapeutic development.
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