Experimental Cell Research[JOURNAL]
Sun
200 papers
High Mobility Group Protein B1 and its downstream elements, syntaxins, contribute to temporal tight junction assembly in a human keratinocyte cell line.
Matsunaga H, Nozaki S, Abe J … +1 more , Hirai Y
Exp Cell Res · 2026 Apr · PMID 41638388 · Publisher ↗
While the epidermis is a stratified epithelium undergoing continuous turnover, tight junctions (TJs), which are critical barrier structures, form transiently and exclusively within specific cells of the upper stratum. Th...
While the epidermis is a stratified epithelium undergoing continuous turnover, tight junctions (TJs), which are critical barrier structures, form transiently and exclusively within specific cells of the upper stratum. The cytoplasmic-to-membrane translocation of ZO-1, a scaffold protein of TJs, accompanies the assembly of TJs. Previously, we demonstrated that a secreted subset of the nuclear protein High Mobility Group Protein B1 (HMGB1) and the type IV membrane protein epimorphin/syntaxin2 (Stx2) impede, whereas the Stx2 paralogue syntaxin3 (Stx3) promotes, the membrane translocation of ZO-1 in HaCaT keratinocytes. In this study, we observed that HMGB1-knockout (HMGB1-KO) increases membrane-localized ZO-1 in only a restricted subset of cells, accompanied by downregulation of both Stx2 and Stx3. Inducible overexpression of exogenously introduced Stx3 significantly accelerates the membrane localization of ZO-1 in most HMGB1-KO cells, accompanied by upregulation of the PRSS3 gene product mesotrypsin, another supportive element for TJ formation, indicating that nuclear HMGB1 abundance regulates TJ assembly, at least partially, through the downregulation of these syntaxins independent of its extracellular secretion. Given that HMGB1, Stx2, Stx3, and mesotrypsin are all known to be transiently extruded into the extracellular space, these observations elucidate a regulatory mechanism underlying the spatiotemporal formation of TJs by these pleiotropic proteins and provide valuable insights into potential therapeutic strategies for inflammatory skin conditions characterized by compromised barrier function.
Targeting miR-499-5p for neuroprotection in spinal cord injury: Implications for inflammation and ROS-induced neuronal damage.
Yang S, Guan Y, Yu Q … +4 more , Zheng C, Xia X, Ma X, Jiang J
Exp Cell Res · 2026 Apr · PMID 41638387 · Publisher ↗
Spinal cord injury (SCI) leads to a cascade of secondary damage responses, including inflammation, apoptosis, and oxidative stress. These processes are crucial in determining the extent of tissue damage and recovery. It...
Spinal cord injury (SCI) leads to a cascade of secondary damage responses, including inflammation, apoptosis, and oxidative stress. These processes are crucial in determining the extent of tissue damage and recovery. It is well-established that various molecular mechanisms, such as the regulation of gene expression by non-coding RNAs, contribute significantly to the pathophysiology of SCI. However, the processes behind miRNA-regulated secondary damage are not entirely understood. The SCI mouse model and the cellular model were developed to investigate the effects of miRNAs during SCI. The GEO miRNA expression profile (GSE158195) was retrieved, and the differentially expressed miRNAs were examined using bioinformatics tools. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to assess the expression levels of miRNA and programmed cell death protein 4 (PDCD4). The Basso, Beattie, and Bresnahan (BBB) scoring system was used to assess neurological function. The concentrations of inflammatory cytokines were quantified via ELISA, whereas the production of reactive oxygen species (ROS) was assessed utilizing commercial kits. Our findings revealed a significant down-regulation of miR-499-5p in the spinal cord tissue of SCI mice. According to the functional study, agomir-miR-499 treatment significantly improved locomotor recovery, reduced tissue damage and edema, and suppressed neuronal death. Agomir-miR-499 also reduced SCI-induced ROS and inflammatory responses in mice. In SCI mice and cell models, miR-499 was discovered to target programmed cell death 4 and regulated its expression at protein and mRNA levels. Furthermore, increasing PDCD4 reversed agomir-miR-499's suppressive effects on the inflammatory response, ROS, and cell death. Agomir-miR-499, meanwhile, has the ability to suppress PDCD4 expression and stimulate the PI3K/AKT signaling pathway in SCI mice. Overall, our research shows that miR-499, a potential therapeutic target for SCI, reduces ROS-induced neuronal death and inflammation through PI3K/Akt signaling in SCI mice.
The Runx2 switch: unlocking osteoblast-related disorders through signaling pathways and non-coding RNAs.
Aslani S, Kalantary-Charvadeh A, Abbasalipourkabir R … +1 more , Ziamajidi N
Exp Cell Res · 2026 Mar · PMID 41621578 · Publisher ↗
Osteoblasts, specialized bone-forming cells, differentiate from mesenchymal stem cells (MSCs). In recent years, stem cell-derived osteoblasts have emerged as potential choices for the treatment of bone-related disorders....
Osteoblasts, specialized bone-forming cells, differentiate from mesenchymal stem cells (MSCs). In recent years, stem cell-derived osteoblasts have emerged as potential choices for the treatment of bone-related disorders. A complex network of regulatory elements, including signaling pathways, transcription factors, and non-coding RNAs (ncRNAs), orchestrates MSCs differentiation. Among the key regulators of osteoblast differentiation is Runt-related transcription factor 2 (Runx2), a master transcription factor essential for osteogenic commitment. Elucidating the molecular mechanisms that regulate Runx2 expression and function is critical for the treatment of osteoblast-related disease. Runx2 is regulated through signaling pathways and a complex, post-transcriptional competing endogenous RNA (ceRNA) network. In this network, circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) sequester microRNAs (miRNAs), thereby fine-tuning Runx2 expression. Signaling pathways can also indirectly regulate Runx2 by inducing the expression of osteo-regulatory miRNAs. This review highlights the regulatory role of Runx2 during osteoblastic differentiation. It also explores how signaling pathways, lncRNAs, circRNAs, and other factors interact with Runx2-regulatory miRNAs involved in this process.
Insulin-like growth factor-1 enhances β-amyloid protein clearance in HMC3 microglia via low-density lipoprotein receptor-related protein 1-mediated pathway.
Guo H, Peng X, Zhang X … +6 more , Ruganzu JB, Wu X, Zhao M, Yang P, Ji S, Yang W
Exp Cell Res · 2026 Apr · PMID 41621577 · Publisher ↗
β-amyloid protein (Aβ) deposition occurs years before cognitive symptoms appear and is considered one of the main causes underlying the pathogenic events that occur in Alzheimer's disease (AD). Mounting evidence suggests...
β-amyloid protein (Aβ) deposition occurs years before cognitive symptoms appear and is considered one of the main causes underlying the pathogenic events that occur in Alzheimer's disease (AD). Mounting evidence suggests that the imbalance of Aβ production and clearance leads to the accumulation of Aβ and the subsequent formation of toxic Aβ aggregates. Aβ is internalized by microglia and transported to lysosomes for degradation, which is one of the main ways by which Aβ may be cleared from the brain. Insulin-like growth factor-1 (IGF-1) promotes clearance of Aβ in the brain by enhancing Aβ carrier proteins. Our previous study demonstrated that low-density lipoprotein receptor-related protein 1 (LRP1) mediates the internalization of Aβ and lysosomal trafficking in primary cortical neurons. However, whether IGF-1 enhances the clearance of Aβ in microglia through the LRP1-mediated pathway and its underlying mechanisms is incompletely understood. Here, we reported that knockdown of LRP1 expression significantly decreased the internalization of Aβ in HMC3 cells. Furthermore, pretreatment with IGF-1 significantly increased intracellular Aβ, indicating IGF-1 enhances HMC3 cells uptake of extracellular Aβ. Interestingly, the intracellular Aβ in LRP1-knockdown HMC3 cells was reduced after preincubation with IGF-1. Thus, it was indicated that LRP1 is essential for IGF-1-enhanced internalization of Aβ in HMC3 cells. Moreover, IGF-1 significantly inhibited the downregulation of PI3K, phospho-PI3K, Akt, and phospho-Akt induced by Aβ. Importantly, treatment with LY294002, a PI3K inhibitor, significantly reduced the intracellular Aβ levels and decreased the expression of LRP1. These findings indicated that IGF-1 enhances the internalization of Aβ in a LRP1-dependent manner by activating the PI3K/Akt signaling pathway. Finally, we identified that IGF-1 promotes lysosomal proteolysis of Aβ by increasing cathepsin B (CTSB) and cathepsin D (CTSD) expression. Consequently, these results demonstrated that IGF-1 promotes the internalization and lysosomal degradation of Aβ by microglia, which is an effective approach to lowering brain Aβ levels, and it might be a promising therapeutic target for AD.
Optimization of a high-efficiency single-cell regeneration system in sugarcane (Saccharum officinarum) via hormonal regulation and physiological characterization.
Su Y, Zhang D, Han S … +3 more , He Z, Li S, Li Z
Exp Cell Res · 2026 Apr · PMID 41621576 · Publisher ↗
Efficient regeneration of plants from single cells is a critical yet challenging step for applying modern biotechnologies to sugarcane (Saccharum spp.), a vital sugar and bioenergy crop. The main obstacles include low em...
Efficient regeneration of plants from single cells is a critical yet challenging step for applying modern biotechnologies to sugarcane (Saccharum spp.), a vital sugar and bioenergy crop. The main obstacles include low embryogenic competence and recalcitrant differentiation. Here, we established a standardized, high-efficiency single-cell regeneration system for the model cultivar ROC22 by systematically optimizing key hormonal and physiological parameters. Embryogenic callus, induced from young leaf sheaths, was used to establish suspension cultures. A homogeneous population of single cells with 58 % viability was isolated via 200-mesh sieve filtration. Dynamic growth analysis identified 2.0 mg L 2,4-dichlorophenoxyacetic acid (2,4-D) as optimal for proliferation, yielding a peak density of 2.4 × 10 cells/mL. The differentiation of compact callus was maximized on medium containing 2.0 mg L 6-benzylaminopurine (6-BA) and 0.5 mg L kinetin (KT), resulting in minimal browning (17.8 %) and large callus clusters (1.52 cm in diameter). Ultimately, a high green plantlet regeneration efficiency of 81.1 % was achieved on a regeneration medium with half-strength MS macronutrients, 3 mg L naphthaleneacetic acid (NAA), and 0.5 mg L 6-BA. This reproducible and efficient system provides a robust platform for genetic transformation and single-cell-based studies in sugarcane.
Augmenting Nrf2 signaling pathway promotes adipocyte differentiation from human embryonic stem cells.
Park MH, Gil D, Han HW … +1 more , Kim JH
Exp Cell Res · 2026 Apr · PMID 41620067 · Publisher ↗
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor best regulating cellular defense mechanisms. However, its role in human adipocyte differentiation remains poorly understoo...
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor best regulating cellular defense mechanisms. However, its role in human adipocyte differentiation remains poorly understood. Here, we investigated the contribution of Nrf2 to adipocyte differentiation using an in vivo teratoma model, a straightforward assay for evaluating the differentiation potential of human embryonic stem cells (hESCs). We found that enhanced Nrf2 signaling, induced by KEAP1 gene deletion in hESCs, increased both the size and area of adipocytes within teratomas. Quantitative transcriptomic analysis of teratomas (TeratoScore) and the Ingenuity Pathway Analysis indicated activation of an adipogenesis-related signaling network, as evidenced by increased expression of FABP4, PPARG, ADIPOQ, and CEBPA in KEAP1-knockout teratomas. Stepwise in vitro differentiation of hESCs into adipocytes further supported a pro-adipogenic role for Nrf2, as shown by increased lipid-droplet accumulation. Notably, we identified PAX3 as a transcriptional target associated with Nrf2 activation, suggesting a potential link between Nrf2 signaling and adipogenic regulation. Together, these findings reveal a previously underappreciated role for Nrf2 in human adipogenesis.
KAT5/8-mediated GPX4 lactylation facilitates ferroptosis and inflammation in diabetic retinopathy.
Zhou Y, Du M
Exp Cell Res · 2026 Mar · PMID 41617054 · Publisher ↗
Diabetes-induced hyperglycemia promotes retinal capillary endothelial cell dysfunction, contributing to diabetic retinopathy. In this study, we reveal that high glucose (HG) drives ferroptosis and inflammation through la...
Diabetes-induced hyperglycemia promotes retinal capillary endothelial cell dysfunction, contributing to diabetic retinopathy. In this study, we reveal that high glucose (HG) drives ferroptosis and inflammation through lactate-mediated GPX4 lactylation. HG conditions enhance glycolysis and lactate production, leading to increased lactylation of GPX4, a process mediated by the acetyltransferases KAT5 and KAT8. GPX4 lactylation reduces its antioxidant function, promoting lipid peroxidation, ferroptosis, and inflammation. Specifically, HG exposure significantly increases malondialdehyde (MDA) levels, decreases GSH levels, and elevates lipid ROS, while simultaneously inducing pro-inflammatory cytokine expression (IL6, TNF, and IL1B). Inhibition of KAT5 and KAT8 markedly reduces GPX4 lactylation, restores redox balance, suppresses ferroptosis, and mitigates inflammation. Collectively, our findings identify KAT5- and KAT8-mediated GPX4 lactylation as a key mechanism underlying HG-induced ferroptosis and inflammation in diabetic retinopathy, highlighting its potential as a promising therapeutic target.
Localisation and organisation of the focal adhesion kinase FAK1 and Simiate inside nuclear speckles.
Dahlhaus R, Braun RJ
Exp Cell Res · 2026 Apr · PMID 41617053 · Publisher ↗
The development of a well-organised genome represents a hallmark in the evolution of species. In mammals, the nucleus of each cell is characterised by the presence of different compartments, among others nuclear speckles...
The development of a well-organised genome represents a hallmark in the evolution of species. In mammals, the nucleus of each cell is characterised by the presence of different compartments, among others nuclear speckles, membrane-less organelles that are self-shaped by liquid droplet-like phase separation. Functioning in the organisation of the transcription and splicing machinery, nuclear speckles are highly dynamic, moving and rearranging within the nucleus according to the needs of the cell. In line with a role of actin dynamics in speckle function, we could previously demonstrate that the actin-binding protein Simiate is not only enriched in nuclear speckles, but also able to associate with nuclear isoforms of the Focal Adhesion Kinase FAK1. Furthermore, nuclear speckles have recently been suggested to consist of specific sub-domains involved in the spatial organisation of chromatin handling and mRNA processing. In this study, we therefore examined the sub-speckular organisation of FAK1 and Simiate in mouse brain slices using three-dimensional reconstructions and stimulated emission depletion (STED) microscopy. While FAK1 is predominantly localised in peripheral areas, Simiate is highly enriched in the core domain. Aside, Simiate is also seen in the surrounding shell, and minor amounts of FAK1 are detected in the core domain. As the number of speckles increases, FAK1 is found to diminish from the core domain, whereas peripheral numbers remain constant. Both proteins, Simiate and FAK1, are organised in spherical clusters, which may occasionally colocalise in peripheral as well as core domains. Although our data obtained from mouse brain slices are merely descriptive, they may suggest for dynamic rearrangement of FAK1.
MT1E binds to LncRNA NEAT1 to regulate SLC39A14-mediated ferroptosis in the pathogenesis of aortic dissection.
Xiao C, Zheng Z, Li M … +2 more , Yang Q, Dai X
Exp Cell Res · 2026 Apr · PMID 41611071 · Publisher ↗
BACKGROUND: Aortic dissection (AD) is a life-threatening vascular disease whose pathogenesis involves dysfunction of vascular smooth muscle cells (VSMCs) and cell death. This study aimed to investigate the role of the MT...
BACKGROUND: Aortic dissection (AD) is a life-threatening vascular disease whose pathogenesis involves dysfunction of vascular smooth muscle cells (VSMCs) and cell death. This study aimed to investigate the role of the MT1E/LncRNA NEAT1/SLC39A14 axis in AD and its molecular mechanism in regulating ferroptosis. METHODS: The correlation between ferroptosis and AD was evaluated using single-sample gene set enrichment analysis (ssGSEA). Weighted gene co-expression network analysis (WGCNA) based on the GSE153434 dataset was performed to identify key modules. Differentially expressed genes were screened through GO, KEGG enrichment analyses, and protein-protein interaction (PPI) network analysis. The functions and interactions of MT1E, LncRNA NEAT1, and SLC39A14 were validated using RT-PCR, Western Blot, immunohistochemistry, Co-IP assay, RIP assay, and luciferase reporter assays. A mouse model was constructed to evaluate the role of MT1E in AD pathological injury and ferroptosis. RESULTS: AD was significantly associated with ferroptosis. WGCNA identified a blue module highly correlated with ferroptosis, and 236 differentially expressed genes were screened. MT1E, LncRNA NEAT1, and SLC39A14 were significantly upregulated in aortic tissues of AD patients. Knockdown of MT1E inhibited AngII-induced VSMC proliferation, migration, and ferroptosis, and restored the expression of VSMC phenotypic transformation markers. MT1E activates NEAT1 expression by forming a complex with YBX1, while MT1E activates NEAT1 through zinc ion release-mediated regulation of SFPQ and NONO. Besides, luciferase reporter assays demonstrated the direct binding of LncRNA NEAT1 to SLC39A14. Overexpression of LncRNA NEAT1 reversed the inhibitory effects of MT1E knockdown on VSMC proliferation, migration, and ferroptosis. Overexpression of SLC39A14 counteracted the effects of MT1E or LncRNA NEAT1 knockdown on VSMCs. Mouse model experiments validated the critical role of MT1E in AD pathological injury and ferroptosis. CONCLUSION: This study reveals that MT1E plays a pivotal role in AD by targeting LncRNA NEAT1 to regulate SLC39A14-mediated ferroptosis. These findings provide novel insights into the molecular mechanisms of AD and offer potential therapeutic targets for related diseases.
Overexpression of biliverdin reductase A leads to ROS-independent sensitization of ovarian adenocarcinoma cells to gemcitabine.
Solárová Z, Danková K, Harvanik P … +5 more , Bober P, Majerová P, Michalková R, Bhide M, Solár P
Exp Cell Res · 2026 Mar · PMID 41581642 · Publisher ↗
AIMS: Biliverdin reductase A (BLVRA) is a key enzyme in bilirubin metabolism, where it reduces biliverdin to bilirubin. Bilirubin is a potent antioxidant that protects cells from oxidative stress. Therefore, reduced or d...
AIMS: Biliverdin reductase A (BLVRA) is a key enzyme in bilirubin metabolism, where it reduces biliverdin to bilirubin. Bilirubin is a potent antioxidant that protects cells from oxidative stress. Therefore, reduced or deregulated BLVRA activity may contribute to increased oxidative DNA damage, which is one of the factors leading to the neoplastic transformation of cells. METHODS: Human ovarian adenocarcinoma A2780 cells were transfected with a PiggyBac vector to achieve BLVRA overexpression. A2780 clones showing the most significant BLVRA gene overexpression were analyzed by proteomics and flow cytometry to assess rective oxygen species (ROS) production. RESULTS: Our results indicate that BLVRA overexpression increases the sensitivity of A2780 cells to doxorubicin and gemcitabine, with the most pronounced effect observed in the J clone. In this clone, the highest level of BLVRA overexpression correlated with significant alterations in the p53 signaling pathway. Upregulation of key effectors such as Bax and CDKN2A indicates a potential role for BLVRA in promoting pro-apoptotic responses. Moreover, BLVRA overexpression increased the sensitivity of A2780 cells to gemcitabine independently of ROS. CONCLUSIONS: This study broadens our understanding of BLVRA in ovarian cancer. In cells with intact p53 signaling, BLVRA overexpression can paradoxically enhance cytotoxic response to certain drugs, particularly gemcitabine.
CDC6 promotes keratinocyte senescence through the CCND1/P53 signaling in ischemia-reperfusion injury-induced pressure injury.
Wang C, Zhu S, Dai M … +1 more , Chen H
Exp Cell Res · 2026 Mar · PMID 41580178 · Publisher ↗
Pressure injuries develop when prolonged compression of the skin and subcutaneous tissue impairs blood circulation, leading to localized tissue ischemia, degeneration, and ultimately necrosis. Ischemia-reperfusion(I/R) i...
Pressure injuries develop when prolonged compression of the skin and subcutaneous tissue impairs blood circulation, leading to localized tissue ischemia, degeneration, and ultimately necrosis. Ischemia-reperfusion(I/R) injury is one of the key pathological mechanisms underlying pressure injury formation. While cellular senescence has been implicated in I/R-related pathologies, its role in pressure injury development remains unclear. We aimed to elucidate the mechanisms of keratinocyte senescence in cutaneous I/R injury. An in vitro hypoxia/reoxygenation (H/R) model was employed to simulate I/R injury using human immortalized keratinocytes (HaCaT). H/R induction significantly exacerbated the senescence response, as characterized by reduced cell proliferation, increased apoptosis, elevated SA-β-galactosidase (SA-β-gal) activity, and upregulated expression of senescence markers (p16 and p21). Quantitative proteomic analysis identified CDC6 as a prominently upregulated protein under H/R conditions. siRNA-mediated CDC6 knockdown attenuated keratinocyte senescence, restored G1/S phase cyclin-D1 (CCND1) expression, and suppressed p53 levels, demonstrating its regulatory role in senescence via the p53/CCND1 pathway. Furthermore, protein interaction network analysis and experimental validation revealed CDC6's direct binding with origin recognition complex 2 (ORC2), evidenced by nuclear colocalization (immunofluorescence) and physical interaction (co-immunoprecipitation). Collectively, our findings pioneers the mechanistic elucidation of CDC6 in pressure injury pathology, proposing senescence-targeted interventions as a novel therapeutic strategy for ulcer management.
Corrigendum to "A human tissue-based model of renal inflammation" [Exp. Cell Res. 2024 Nov 1;443(1):114309].
Merrild C, Pedersen GA, Antonsen KW … +6 more , Madsen MG, Keller AK, Møller HJ, Nejsum LN, Mutsaers HAM, Nørregaard R
Exp Cell Res · 2026 Mar · PMID 41571511 · Publisher ↗
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PLA2R1-mediated ERK-Dependent ferroptosis: A key pathogenic mechanism in epileptic neuronal injury.
Chen H, Wu G, Song Q
Exp Cell Res · 2026 Mar · PMID 41565047 · Publisher ↗
BACKGROUND: Phospholipase A2 receptor 1 (PLA2R1) plays a regulatory role in pathological processes, but its mechanism in epileptic neuronal injury remains unclear. This study aimed to elucidate how PLA2R1 promotes epilep...
BACKGROUND: Phospholipase A2 receptor 1 (PLA2R1) plays a regulatory role in pathological processes, but its mechanism in epileptic neuronal injury remains unclear. This study aimed to elucidate how PLA2R1 promotes epileptic neuronal injury through ERK-dependent ferroptosis. METHODS: A kainic acid-induced epilepsy mouse model was employed. PLA2R1 expression was detected using qRT-PCR, Western blot, and immunofluorescence. PLA2R1 knockdown and overexpression vectors were constructed to observe effects on seizure severity and neuronal injury. Ferroptosis indicators (GPX4, ACSL4, PTGS2, MDA, ROS, GSH) were analyzed. HT22 cells were used for in vitro validation with glutamate and Erastin-induced ferroptosis. ERK pathway involvement was verified using inhibitor SCH772984. RESULTS: PLA2R1 was upregulated in epileptic tissues. PLA2R1 knockdown prolonged seizure latency, reduced seizure intensity, decreased neuronal injury, and inhibited ERK activation. It upregulated GPX4 and GSH while downregulating ACSL4, PTGS2, MDA, and ROS. PLA2R1 overexpression exacerbated ferroptosis-related neuronal injury. In vitro experiments confirmed that ferroptosis inducers upregulated PLA2R1, while knockdown improved neuronal survival. ERK inhibitor SCH772984 reversed PLA2R1 overexpression-induced neuronal injury. CONCLUSION: This study identified the PLA2R1-MEK-ERK-ferroptosis signaling axis, suggesting that PLA2R1 contributes to neuronal ferroptosis through ERK pathway activation in epilepsy. PLA2R1's druggability and ERK inhibitors' clinical safety provide foundation for therapeutic translation.
Upregulation of Gfi1 induced by LSD1 inhibitor protects against cisplatin-induced ototoxicity through attenuating pyroptosis.
Zhao Z, Luo J, Ma D … +9 more , Li S, Cen S, Fan H, Hou Z, Lu J, Cheng C, Qian X, Gao X, Li A
Exp Cell Res · 2026 Mar · PMID 41565046 · Publisher ↗
Cisplatin, a widely used chemotherapeutic agent, is associated with significant ototoxicity. Identifying potential therapeutic targets to mitigate cisplatin-induced hearing loss has become a crucial goal. In this study,...
Cisplatin, a widely used chemotherapeutic agent, is associated with significant ototoxicity. Identifying potential therapeutic targets to mitigate cisplatin-induced hearing loss has become a crucial goal. In this study, we demonstrated that the LSD1 inhibitor S2101 could protect against cisplatin-induced ototoxicity (CIO) by upregulating Gfi1 expression. Mechanistically, we investigated the regulatory relationship between Gfi1 and Trim27. Our findings indicated that Gfi1 could bind to the Trim27 promoter region, activating its transcription. The subsequent upregulation of Trim27 significantly attenuated hair cell pyroptosis, highlighting the therapeutic potential of the Gfi1-Trim27 pathway. These results collectively underscore the critical function of Gfi1 in protecting against cisplatin-induced hearing loss and provide novel insights into potential therapeutic strategies.
AHNAK inhibits osteoporosis progression by stabilizing Smad1 protein.
Zhang W, Chen H, Qi T … +5 more , Yao D, Liu H, Zeng H, Yu F, Zhou W
Exp Cell Res · 2026 Mar · PMID 41554467 · Publisher ↗
AHNAK is a structural scaffold protein implicated in a wide array of physiological functions. AHNAK mutations are highly prevalent in patients with osteoporosis, However, it is currently unknown whether AHNAK affects the...
AHNAK is a structural scaffold protein implicated in a wide array of physiological functions. AHNAK mutations are highly prevalent in patients with osteoporosis, However, it is currently unknown whether AHNAK affects the progression of osteoporosis and the specific mechanism behind this effect. This study detected decreased AHNAK (AHNAK1) expression in bone tissues and bone marrow mesenchymal stem cells (BMSCs) of osteoporotic mice. Genetic knockdown of AHNAK inhibited osteogenic differentiation of BMSCs. Mechanistic investigations indicated that AHNAK functions through stabilizing Smad1 protein levels. Overexpression of Smad1 in AHNAK-knockdown BMSCs restored their osteogenic differentiation capacity. Furthermore, in vivo mouse experiments further confirmed these findings. Collectively, these findings indicate that AHNAK inhibits the progression of osteoporosis by stabilizing Smad1 protein.
USP18 promotes cell proliferation and inhibits ferroptosis by stabilizing HDAC3 in endometrial carcinoma.
Tong F, Gao X, Shang Y
Exp Cell Res · 2026 Mar · PMID 41547495 · Publisher ↗
Endometrial cancer (EC) represents one of the most prevalent malignancies of the female reproductive system. Ferroptosis, a recently identified form of programmed cell death, has garnered increasing attention in cancer r...
Endometrial cancer (EC) represents one of the most prevalent malignancies of the female reproductive system. Ferroptosis, a recently identified form of programmed cell death, has garnered increasing attention in cancer research. Ubiquitin-specific peptidase 18 (USP18), a member of the deubiquitinating enzyme family, has been recognized as an oncoprotein in various cancers; however, its functional role and underlying mechanisms in EC remain largely unexplored. In this study, we found that USP18 was markedly upregulated in EC patients (n = 15, stage I; n = 4, stage II and n = 1, stage III), and elevated USP18 expression correlated with unfavorable prognosis. Functional assays demonstrated that knockdown of USP18 significantly inhibited EC cell proliferation. Moreover, USP18 silencing promoted the accumulation of lipid reactive oxygen species (ROS), malondialdehyde (MDA), and Fe, thereby enhancing erastin-induced ferroptosis. In contrast, USP18 overexpression produced opposing effects. These in vitro findings were further validated in vivo, where USP18 knockdown suppressed tumor growth and promoted ferroptosis. Mechanistic investigations revealed that USP18 interacted with and deubiquitinated histone deacetylase 3 (HDAC3), thus leading to its stabilization. Subsequent rescue experiments confirmed that the tumor-promoting effects of USP18 were abrogated upon HDAC3 knockdown. Taken together, our results identify the USP18/HDAC3 axis as a key regulator of EC cell proliferation and ferroptosis suppression, underscoring the potential of USP18 as a therapeutic target in EC.
Upregulation of EphA2 by Src counteracts Src-induced loss of cell adhesion.
Takada M, Murata M, Soeda S … +3 more , Honda T, Yuki R, Nakayama Y
Exp Cell Res · 2026 Mar · PMID 41544877 · Publisher ↗
The receptor tyrosine kinase EphA2 is highly expressed in various cancers, and its elevated levels are associated with poor prognosis. Although Src has been shown to increase EphA2 expression partly through ERK signaling...
The receptor tyrosine kinase EphA2 is highly expressed in various cancers, and its elevated levels are associated with poor prognosis. Although Src has been shown to increase EphA2 expression partly through ERK signaling, the functional consequences of EphA2 upregulation remain unclear. In this study, we investigated the role of EphA2 upregulation by active Src in cell adhesion. We utilized HeLa S3-derived HeLa S3/v-Src cells, which allow inducible v-Src expression upon doxycycline (Dox) treatment. Dox treatment induced v-Src expression, cell rounding, and a marked increase in global tyrosine phosphorylation. Consistent with previously reports, EphA2 expression was upregulated following v-Src induction. Time-course analysis revealed that EphA2 knockdown accelerated v-Src-induced cell rounding. Similarly, c-Src also upregulated EphA2 and induced cell rounding. Paxillin staining demonstrated that c-Src expression increased both the number and area of focal adhesions, as well as paxillin intensity at these sites. All of these effects were abolished by EphA2 knockdown. In conclusion, Src activity upregulates EphA2 expression, and increased EphA2 counteracts Src-induced cell detachment. However, as Src signaling intensifies, it overrides the counteracting effect of EphA2, resulting in cell rounding and detachment. The balance between Src and EphA2 may act as a key regulator of cellular adhesion dynamics.
Epigenetic mechanism of LncRNA KCNQ1OT1 in high-glucose-induced podocyte injury via m6A methylation modification.
Hou Y, Wang D, Liu L … +3 more , Tian J, Zhi M, Shi Y
Exp Cell Res · 2026 Mar · PMID 41539350 · Publisher ↗
Podocyte injury is a hallmark of diabetic nephropathy associated with proteinuria and renal dysfunction. This study elucidated the role of long non-coding RNA KCNQ1 overlapping transcript 1 (LncRNA KCNQ1OT1) in high-gluc...
Podocyte injury is a hallmark of diabetic nephropathy associated with proteinuria and renal dysfunction. This study elucidated the role of long non-coding RNA KCNQ1 overlapping transcript 1 (LncRNA KCNQ1OT1) in high-glucose (HG)-induced podocyte injury. In HG-treated podocytes, KCNQ1OT1, WTAP, and MAPK6 were quantified. After KCNQ1OT1 interference, cell viability, apoptosis, inflammation, and oxidative stress were measured. Subcellular localization of KCNQ1OT1 was determined by nuclear-cytoplasmic fractionation and RNA FISH. Binding of MLL1 to KCNQ1OT1 was validated via RNA pull-down and RIP. MLL1/H3K4me3 enrichment on the WTAP promoter was detected by ChIP. m6A levels of MAPK6 were measured by MeRIP. Binding of IGF2BP1 to MAPK6 was confirmed via RIP. Rescue experiments explored the WTAP/MAPK6 axis in podocyte injury. HG treatment upregulated KCNQ1OT1, WTAP, and MAPK6 in podocytes. KCNQ1OT1 knockdown enhanced cell proliferation, reduced apoptosis, and attenuated inflammation and oxidative stress. Mechanistically, nuclear-localized KCNQ1OT1 recruited MLL1 to the WTAP promoter, enhancing H3K4me3 modification and WTAP activation. WTAP promoted m6A methylation of MAPK6 mRNA, which was stabilized by IGF2BP1. Overexpression of WTAP or MAPK6 abrogated the protective effects of KCNQ1OT1 knockdown on podocytes injury. In conclusions, KCNQ1OT1 exacerbates HG-induced podocyte injury by upregulating the WTAP/MAPK6 axis in an m6A-dependent manner.
Phosphofructokinase in glycolysis: Bridging enzymology and cell biology.
Sharma A, An S
Exp Cell Res · 2026 Mar · PMID 41520947 · Publisher ↗
ATP-dependent phosphofructokinase (PFK) catalyzes a key committed step in glycolysis. Also called the "gatekeeper" of glycolysis, PFKs catalyze an irreversible phosphorylation of fructose-6-phosphate to fructose-1,6-bisp...
ATP-dependent phosphofructokinase (PFK) catalyzes a key committed step in glycolysis. Also called the "gatekeeper" of glycolysis, PFKs catalyze an irreversible phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. While eukaryotic PFKs are more than double the size of prokaryotic PFKs, the overall structure and mechanism of PFKs are largely conserved from prokaryotes to eukaryotes. Usually tetrameric to be active, PFKs are also found to form higher-order structures, such as octamers in yeasts and multimeric filaments in mammals. Due to their central role in glycolysis, the enzymatic activity of PFKs is highly regulated by a myriad of allosteric effectors, post-translational modifications, and various signaling pathways. Such complex regulatory networks of PFKs often result from and/or result in a variety of protein-protein interactions, thus providing the molecular basis of dynamic association and dissociation of PFKs into multienzyme metabolic assemblies (i.e., metabolons) in cells. The concept of metabolon has now become an organizational principle for a cell to regulate the function of PFKs and thus govern glycolysis. Therefore, this article aims to integrate current knowledge in PFK enzymology and cell biology to provide a molecular and cellular framework for repositioning this century-old drug target for innovative therapeutic applications.
S-nitrosylated COX-2 is a microenvironment-regulated breast cancer cell biomarker of mesenchymal phenotypes.
Hoffmann RJ, Bensen A, Dane M … +4 more , Arterberry J, Smith R, Korkola J, Schedin P
Exp Cell Res · 2026 Mar · PMID 41512995 · Full text
COX-2, an inducible enzyme key to production of inflammatory prostaglandins, has tumor cell-intrinsic oncogenic activity. Previously, we reported Cys-526-nitrosylated COX-2 (SNO-COX-2) associates with breast cancer progr...
COX-2, an inducible enzyme key to production of inflammatory prostaglandins, has tumor cell-intrinsic oncogenic activity. Previously, we reported Cys-526-nitrosylated COX-2 (SNO-COX-2) associates with breast cancer progression and poor-prognostic young onset breast cancer. Here, using a 3D culture model of early-stage human breast cancer (MCF10DCIS cells), we report SNO-COX-2, but not non-nitrosylated COX-2, closely associated with mesenchymal cell phenotypes induced by fibrillar Col1. Inhibition of nitric oxide synthase (NOS) activity did not reduce SNO-COX-2 levels, suggesting alternative nitrosylation mechanisms. In 3D MCF10DCIS culture, mesenchymal phenotypes and SNO-COX-2 protein induced by Col1 did not associate with transcription of classic epithelial-to-mesenchymal transition (EMT) markers nor common cancer signaling pathways. Conversely, TGFβ-1 strongly induced EMT- and cancer signaling-related transcripts but was insufficient to increase SNO-COX-2 protein or mesenchymal phenotypes. These data suggest the mesenchymal phenotype and SNO-COX-2 expression in MCF10DCIS are driven by a non-transcriptional mechanism dependent on Col1. We tested 300 additional microenvironmental conditions and find SNO-COX-2 expression is driven by inflammatory, wound-resolving, and cancer-associated TME factors, including TNC, SPP1, decorin, Col1, Col3, INF-γ, and IL-4/13, with specific extracellular matrix-ligand combinations driving both high and low SNO-COX-2 expression. In sum, these observations show that in MCF10DCIS cells, SNO-COX-2 associates with mesenchymal phenotypes more strongly than non-nitrosylated COX-2; expression of classic EMT transcripts is neither sufficient nor necessary for acquisition of mesenchymal phenotypes; and expression of SNO-COX-2 is highly microenvironment-dependent. Future studies evaluating SNO-COX-2 as a biomarker for early-stage breast cancer with increased risk for progression, and its regulation, are warranted.
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