J. Cell. Physiol. [JOURNAL]
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200 papers
Mt1-Ca-Mitochondrial Metabolic Axis Maintains Temporomandibular Joint Condylar Cartilage Homeostasis Under Low Oxygen and Hypoxic Condition.
Yan Y, Jia F, Gao Z … +2 more , Liang C, Geng W
J Cell Physiol · 2026 Jun · PMID 42376695 · Publisher ↗
The adaptive capacity of chondrocytes to fluctuating oxygen levels during the process of osteoarthritis remains poorly understood. This study aimed to investigate the role and underlying mechanisms of the Mt1-Ca-mitochon...
The adaptive capacity of chondrocytes to fluctuating oxygen levels during the process of osteoarthritis remains poorly understood. This study aimed to investigate the role and underlying mechanisms of the Mt1-Ca-mitochondrial metabolic axis in chondrocyte function and cartilage homeostasis. Primary rat condylar chondrocytes were cultured under physiological low oxygen (5% O) and hypoxia (<1% O) with Mt1 knockdown or overexpression. The role of Mt1 in chondrocyte functions were investigated. Transcriptomic analysis identified intracellular Ca and metabolism-related pathways regulated by Mt1. Mitochondrial respiration and glycolytic capacity were evaluated by Seahorse XF assays, while intracellular Ca concentration was quantified by Calcium Assay Kit. The effects of extracellular Ca supplementation were analyzed to clarify the Mt1-Ca interaction in metabolic regulation. In vivo, a rat model with intra-articular Mt1 knockdown and chronic sleep deprivation-induced hypoxia was established to verify the role of Mt1 in condylar cartilage homeostasis. Mt1 expression was significantly upregulated under hypoxia and positively correlated with chondrocyte viability, migration, and extracellular matrix synthesis. RNA-seq and enrichment analyses revealed that Mt1 regulates genes associated with mitochondrial respiration and Ca binding. Mt1 knockdown significantly downregulated intracellular Ca, which were restored by extracellular Ca supplementation. Seahorse analysis demonstrated that Mt1 knockdown significantly suppressed mitochondrial respiration and glycolytic capacity, whereas extracellular Ca supplementation restored these deficits. In vivo, Mt1 knockdown aggravated condylar cartilage degeneration, which was further exacerbated under chronic sleep deprivation-induced hypoxia, as evidenced by surface erosion, matrix loss, and histological disorganization. Mt1 preserves TMJ condylar chondrocyte homeostasis under low oxygen and hypoxic conditions by coordinating mitochondrial and glycolytic metabolism through Ca regulation. The Mt1-Ca-mitochondrial metabolic axis serves as a key adaptive mechanism sustaining cellular energy homeostasis and represents a potential therapeutic target for preventing temporomandibular joint osteoarthritis.
Correction to "IRE1α/NOX4 Signaling Pathway Mediates Ros-Dependent Activation of Hepatic Stellate Cells in NaAsO-Induced Liver Fibrosis".
J Cell Physiol · 2026 Jun · PMID 42367051 · Publisher ↗
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Lipocalin-2 Restores Mitochondrial and Antioxidant Adaptation in a Strain-Specific Manner During LPS Induced Sepsis.
Kushwaha V, Kandalgaonkar MR, Singh S … +4 more , Saha P, Kumar A, Yeoh BS, Vijay-Kumar M
J Cell Physiol · 2026 Jun · PMID 42366650 · Full text
Sepsis induces profound metabolic and mitochondrial dysfunction, contributing to multiple organ injury and mortality. Lipocalin-2 (Lcn2), an acute-phase protein, regulates iron homeostasis and oxidative stress, but its i...
Sepsis induces profound metabolic and mitochondrial dysfunction, contributing to multiple organ injury and mortality. Lipocalin-2 (Lcn2), an acute-phase protein, regulates iron homeostasis and oxidative stress, but its impact on mitochondrial resilience remains poorly understood. Here, we investigated the role of Lcn2 in modulating mitochondrial function and hepatic stress responses in C57BL/6 J (BL6) and BALB/c mice in LPS-induced endotoxemia. Lcn2-deficient (Lcn2KO) mice exhibited reduced basal respiration, maximal respiration, and spare respiratory capacity, indicating impaired mitochondrial oxidative phosphorylation. Administration of recombinant Lcn2 (rLcn2) restored mitochondrial respiration in both mouse strains under basal conditions; however, during LPS challenge, only BL6 mice partially preserved mitochondrial function, whereas BALB/c mice remained compromised. To explore underlying mechanisms, we assessed hepatic gene expression by qRT-PCR. LPS induced Acyl-CoA synthetase long-chain family member 4 (ACSL4) and suppressed lysophosphatidylcholine acyltransferase 3 (LPCAT3), markers associated with lipid remodeling, as well as altered antioxidant genes glutathione peroxidase 4 (GPX4) and superoxide dismutase 2 (SOD2) in both strains. rLcn2 treatment in BL6 mice normalized ACSL4 and LPCAT3 expression and enhanced antioxidant gene transcription, whereas BALB/c mice showed minimal recovery. In BL6 mice, Lcn2 supports oxidative phosphorylation while simultaneously modulating lipid metabolism and antioxidant defenses, highlighting its integrated role in cellular adaptation to endotoxemia. Our results reveal that differential Lcn2 responsiveness contributes to inter-strain variation in susceptibility to sepsis-induced mitochondrial dysfunction and identify Lcn2 as a potential therapeutic target for enhancing metabolic resilience during sepsis.
Dysregulation of Non-Muscle Myosin IIA Assembly and Phosphorylation in S100A4 Null Mouse Lens.
Maddala R, Lankford LK, Skiba NP … +1 more , Rao PV
J Cell Physiol · 2026 Jun · PMID 42312500 · Full text
Non-muscle myosin IIA (NMIIA), a motor protein plays a critical role in regulating cell morphology, adhesion, migration, contractility, and mechanotransduction across various tissues, including the ocular lens. S100A4, a...
Non-muscle myosin IIA (NMIIA), a motor protein plays a critical role in regulating cell morphology, adhesion, migration, contractility, and mechanotransduction across various tissues, including the ocular lens. S100A4, a known NMIIA-interacting protein, is abundantly expressed and exhibits a discrete spatial distribution in lens fibers. Loss of S100A4 has previously been shown to associate with late-onset lens opacification in mice. However, its role in regulating NMIIA activity, assembly, and actin cytoskeletal organization in the lens remains unclear. Using S100A4-null mice, this study reveals that S100A4 co-immunoprecipitates with NMIIA and that its absence leads to decreased NMIIA (Ser1943) phosphorylation, impaired NMIIA filament assembly, and disruption in actin cytoskeletal organization and polymerization in the lens. Quantitative proteomic analysis further identified decreased levels of CLIC5 and RNA binding protein-SERBP1 in cytoskeletal- and membrane-enriched fractions from S100A4-null versus wild-type lenses. Moreover, treatment of wild-type mouse lenses in ex-vivo with trifluoperazine, a known S100A4 inhibitor, induced lens opacification in association with increased insolubilization of S100A4, NMIIA and actin. Collectively, these findings demonstrate that S100A4 plays a critical role in regulating NMIIA activity and assembly, and maintaining actin cytoskeletal organization in the ocular lens, thereby contributing to lens transparency and homeostasis.
Corrigendum to "A Probiotic Combination of Limosilactobacillus reuteri and Clostridium butyricum Ameliorates 5-Fluorouracil-Induced Intestinal Mucositis in Rats by Strengthening Barrier Integrity and Modulating Immuno-Microbial Homeostasis".
Ou CC
J Cell Physiol · 2026 Jun · PMID 42290542 · Publisher ↗
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Sexually Dimorphic Regulation of MiR-29a/c-3p in Human Endothelial Cells: Cell Functions and Transcriptome.
Zhang SY, Freel CI, Zhou C … +1 more , Zheng J
J Cell Physiol · 2026 Jun · PMID 42290056 · Full text
Preeclampsia (PE) is a major cause of maternal and fetal morbidity and mortality during pregnancy. PE is characterized by widespread endothelial dysfunction in mothers and fetuses. The etiology of PE remains elusive, but...
Preeclampsia (PE) is a major cause of maternal and fetal morbidity and mortality during pregnancy. PE is characterized by widespread endothelial dysfunction in mothers and fetuses. The etiology of PE remains elusive, but the dysregulation of microRNAs (miRNAs) in endothelial cells may contribute to the pathogenesis of PE. We have reported that PE downregulates expression of two miRNAs, miR-29a-3p and miR-29c-3p (miR-29a/c-3p), and knockdown of miR-29a/c-3p impairs functions of human umbilical vein endothelial cells (HUVECs). Herein, we tested the hypothesis that knockdown of miR-29a/c-3p sex-specifically impairs cellular responses to vascular endothelial growth factor-A (VEGFA) and fibroblast growth factor 2 (FGF2) via disrupting the transcriptome in HUVECs. MiR-29a/c-3p were knocked down using miR-29c-3p inhibitors in male and female HUVECs. Chemotactic and proliferative responses to VEGFA and FGF2 were assessed. RNA-seq was performed to identify miR-29a/c-3p regulated genes and pathways. Knockdown analysis demonstrated that miR-29c-3p inhibitors decreased miR-29a/c-3p levels by over 95% in male and female HUVECs. Functionally, miR-29c-3p inhibitors suppressed VEGFA-, but not FGF2-stimulated chemotaxis by 26% in male, but not female HUVECs. RNA-seq revealed that miR-29a/c-3p inhibitors dysregulated 47 and 118 genes in male and female HUVECs, respectively. Bioinformatics analyses showed that miR-29a/c-3p-regulated genes were differently associated with hypertension, heart, angiogenesis, and immunology in male and female HUVECs. These data demonstrate that knockdown of miR-29a/c-3p sex-specifically affects cellular responses to VEGFA and FGF2 in HUVECs, possibly via disrupting the transcriptome and relevant pathways. These miR-29a/c-3p-regulated genes might represent promising sex-specific therapeutic targets for PE-associated endothelial dysfunction pending further in vivo and clinical verification.
Immune Evasion in Ovarian Cancer Peritoneal Metastasis: Mechanisms and Biomarker-Guided Therapeutic Matching.
Wang X, Wang J, Xiong D … +6 more , Cui S, Wang Q, Huang Y, Ding G, Tang Y, Feng Y
J Cell Physiol · 2026 Jun · PMID 42252670 · Full text
Ovarian cancer peritoneal metastasis remains a major cause of recurrence and death despite advances in cytoreductive surgery, platinum-based chemotherapy, PARP inhibition, and immune checkpoint blockade. The limited acti...
Ovarian cancer peritoneal metastasis remains a major cause of recurrence and death despite advances in cytoreductive surgery, platinum-based chemotherapy, PARP inhibition, and immune checkpoint blockade. The limited activity of immunotherapy in this setting reflects layered immune resistance shaped by impaired antigen visibility, redundant inhibitory receptor networks, suppressive myeloid and regulatory circuits, and metabolic-epigenetic constraints within ascites and multicellular spheroids. These compartment-specific features distinguish peritoneal disease from anatomically confined tumors and help explain why systemic immune reinvigoration alone rarely produces durable benefit. Here, we synthesize current evidence on the mechanisms that govern immune escape in ovarian cancer peritoneal dissemination, with emphasis on antigen presentation defects, checkpoint-driven T-cell exhaustion, anti-phagocytic signaling, soluble suppressive mediators, and metabolic remodeling of the ascites microenvironment. We further examine how DNA damage response states intersect with innate immune sensing and discuss the translational implications of homologous recombination deficiency for combination treatment design. Finally, we propose a biomarker-guided framework that links antigen-presentation competence, immune engagement, dominant suppressive axes, and ascites-specific biology to rational therapeutic matching. This mechanism-centered view supports more precise trial design and provides a roadmap for combination immunotherapy in advanced ovarian cancer.
The ABHD10-KCMF1 Complex Mitigates Cochlear Aging by Regulating Mitochondrial Lipid Metabolism.
Peng L, Liao X, Liu Y … +5 more , Qiu C, Tang Z, Huang Z, Liao H, Yin S
J Cell Physiol · 2026 May · PMID 42206676 · Publisher ↗
Presbycusis is caused by multiple factors, the mechanisms of which are not fully understood. This study investigated mitochondria-related genes in presbycusis, a condition with multifactorial and incompletely understood...
Presbycusis is caused by multiple factors, the mechanisms of which are not fully understood. This study investigated mitochondria-related genes in presbycusis, a condition with multifactorial and incompletely understood mechanisms, by combining Mendelian randomization analysis and functional validation. Genetically predicted higher ABHD10 expression was identified as a protective factor against presbycusis and was regulated by methylation sites such as cg15684481, whereas methylation at other sites inhibited ABHD10 expression and alleviated the condition. In contrast, ABHD10 was upregulated in d-galactose-induced HEI-OC1 cells and aged mouse cochlear hair cells, where it promoted senescence. Silencing ABHD10 in senescent cells reduced P21 and P16 protein levels, decreased reactive oxygen species levels, improved mitochondrial membrane potential, and lowered lipid droplet formation along with triglycerides and fatty acids. Co-immunoprecipitation experiments showed that ABHD10 interacts with KCMF1, indicating that the complex may regulate cellular metabolism and stress responses through signaling pathways. This was supported by GO and KEGG analyses linking ABHD10 to aging-related processes such as energy metabolism and oxidative stress. Overall, ABHD10 functions as a context-dependent mitochondrial regulator, with the ABHD10-KCMF1 axis integrating mitochondrial quality control, lipid homeostasis, and redox balance, thereby offering a potential druggable target for presbycusis.
Serum- and Glucocorticoid-Regulated Kinase 1 Regulates Spindle Assembly Through RanBP1 During Oocyte Meiosis.
Li LS, Yang SJ, Li XQ … +1 more , Duan X
J Cell Physiol · 2026 May · PMID 42206511 · Publisher ↗
Advanced maternal age is associated with increased oocyte aneuploidy and early miscarriage. Serum- and glucocorticoid-regulated kinase 1 (SGK1), a member of the serine/threonine kinase family, is downregulated in oocytes...
Advanced maternal age is associated with increased oocyte aneuploidy and early miscarriage. Serum- and glucocorticoid-regulated kinase 1 (SGK1), a member of the serine/threonine kinase family, is downregulated in oocytes from aged mice. However, the mechanisms by which SGK1 controls oocyte maturation remain unclear. Here, we show that SGK1 localizes predominantly to spindle poles during oocyte maturation. Knockdown of SGK1 via siRNA or pharmacological inhibition disrupts spindle assembly and impairs kinetochore-microtubule attachments in mouse oocytes. This disruption leads to sustained activation of the spindle assembly checkpoint, failure of Cyclin B1 and Securin degradation, impaired metaphase I-anaphase transition, and defective first polar body extrusion. Mechanistically, we identify RanBP1 as a potential mediator of SGK1 function during meiotic progression. In porcine oocytes, SGK1 inhibition similarly compromises maturation and Cyclin B1 degradation, suggesting a conserved role across mammalian species. Together, our findings establish SGK1 as a critical regulator of spindle assembly and meiotic progression in mammalian oocytes.
The Role of Epithelial-Mesenchymal Transition in Oral Inflammatory Diseases.
Wang Y, Yang Y, Xu C … +4 more , Shi P, Wang J, Ding Y, Xie X
J Cell Physiol · 2026 May · PMID 42204904 · Publisher ↗
Epithelial-mesenchymal transition (EMT) refers to a process in which epithelial cells shed their polarity and intercellular adhesion while adopting mesenchymal traits. Emerging evidence indicates that EMT is critically i...
Epithelial-mesenchymal transition (EMT) refers to a process in which epithelial cells shed their polarity and intercellular adhesion while adopting mesenchymal traits. Emerging evidence indicates that EMT is critically involved in the pathogenesis of several oral inflammatory diseases, including periodontitis, drug-induced gingival overgrowth, and Sjögren's syndrome. A thorough understanding of the molecular mechanisms governing EMT may help elucidate the pathogenesis of these diseases and provide new diagnostic and therapeutic strategies for clinical practice. This review will focus on the recent research progress regarding the role of EMT in the above three oral inflammatory diseases, with the aim of offering insights for related research and clinical applications.
Modeling and Characterization of Intestinal Senescence Using Human Organoids: Insights Into the Epithelial to Mesenchymal Transition.
Ayabe T, Takahashi Y, Lee IT … +3 more , Kokubo T, Yamauchi Y, Sato R
J Cell Physiol · 2026 May · PMID 42187232 · Publisher ↗
Intestinal senescence is an important factor in systemic aging and age-related diseases; however, detailed studies have been limited due to the lack of robust experimental models. In this study, we established cellular s...
Intestinal senescence is an important factor in systemic aging and age-related diseases; however, detailed studies have been limited due to the lack of robust experimental models. In this study, we established cellular senescence models of human small intestinal organoids using two senescence-inducing agents: butyrate (an endogenous microbial metabolite) and cisplatin (an exogenous chemotherapeutic agent). Both molecules induced senescence-associated features, including increased p16INK4a, CDKN1A, IL8, and TNF expression, as well as SA-β-Gal activity. RNA-sequencing revealed that cisplatin, but not butyrate, activated the p53 signaling pathway, whereas both downregulated various nutrient absorption and metabolism-related pathways. These models exhibited reduced nutrient transporter expression, diminished glucose uptake, and decreased vitamin D responsiveness, thus recapitulating the features of aged or damaged intestinal tissue. In cisplatin-treated organoids, epithelial to mesenchymal transition (EMT)-related gene ontologies were enriched based on RNA-sequencing. The induction of EMT through cisplatin-induced senescence was further confirmed by EMT marker gene expression, which decreased following the inhibition of TGF-β signaling, a canonical EMT-inducing pathway. Notably, TGF-β signaling inhibition attenuated senescence-induced inflammation and nutrient dysfunction, which suggests the importance of EMT as a target for preventing intestinal senescence. Our models provide a novel platform for examining the intestine-specific molecular mechanisms of senescence associated with distinct senescence-inducing mechanisms and for developing strategies to prevent age-related intestinal dysfunction.
A Probiotic Combination of Limosilactobacillus reuteri and Clostridium butyricum Ameliorates 5-Fluorouracil-Induced Intestinal Mucositis in Rats by Strengthening Barrier Integrity and Modulating Immuno-Microbial Homeostasis.
Leong PY, Chuang WC, Ko JL … +4 more , Liao JW, Chen LC, Tsai YH, Ou CC
J Cell Physiol · 2026 May · PMID 42159170 · Publisher ↗
5-fluorouracil (5FU)-induced intestinal mucositis significantly limits its clinical utility and compromises patient outcomes. Building on our previous finding that a specific probiotic formulation, consisting of Limosila...
5-fluorouracil (5FU)-induced intestinal mucositis significantly limits its clinical utility and compromises patient outcomes. Building on our previous finding that a specific probiotic formulation, consisting of Limosilactobacillus reuteri BCRC 80379 and Clostridium butyricum MIYAIRI 588 (collectively referred to as LCs), mitigated cisplatin-induced mucositis, this study evaluated the prophylactic efficacy and underlying mechanisms of LCs against 5FU-induced mucositis in Wistar rats. Rats were divided into control, 5FU-only, and 5FU+LCs groups. LCs was orally administered daily for 21 days before and throughout the 5FU treatment (50 mg/kg/day for 5 days). Intestinal tissues were analyzed using histological, molecular, and microbiological approaches. Pretreatment with LCs significantly attenuated 5FU-induced small intestinal damage, as evidenced by improved mucosal structure (e.g., increased villus height, crypt depth, and goblet cell density), along with reduced inflammatory cell infiltration. Moreover, LCs reinforced the intestinal barrier by upregulating genes associated with the mucus layer (Muc2) and tight junctions (Ocln, Tjp1, and Cldn1). LCs also suppressed the TLR4/MyD88/NF-κB pathway, leading to reduced levels of pro-inflammatory mediators (e.g., TNF-α, IL-1β, and MPO) while elevating key regulatory mediators such as IL-10 and secretory IgA (sIgA). Furthermore, microbial profiling revealed that LCs beneficially reshaped gut microbiota composition by reducing opportunistic pathogens (e.g., Escherichia-Shigella and Enterobacter). These microbial changes were accompanied by a favorable immune modulation, including decreased pro-inflammatory markers and increased homeostatic mediators. Collectively, these findings suggest that LCs mitigates 5FU-induced mucositis through coordinated regulation of intestinal barrier integrity, immune responses, and gut microbiota, highlighting its potential as a probiotic-based approach for managing chemotherapy-induced intestinal injury.
RETRACTION: Notch Activation Promotes Osteoblast Mineralization by Inhibition of Apoptosis.
J Cell Physiol · 2026 May · PMID 42159055 · Publisher ↗
Y. Xu, B. Shu, Y. Tian, M. Chelly, M.M. Morandi, S. Barton, X. Shang, and Y. Dong, "Notch Activation Promotes Osteoblast Mineralization by Inhibition of Apoptosis," Journal of Cellular Physiology 233, no. 10 (2018): 6921...
Y. Xu, B. Shu, Y. Tian, M. Chelly, M.M. Morandi, S. Barton, X. Shang, and Y. Dong, "Notch Activation Promotes Osteoblast Mineralization by Inhibition of Apoptosis," Journal of Cellular Physiology 233, no. 10 (2018): 6921-6928, https://doi.org/10.1002/jcp.26592. The above article, published online on April 25, 2018, in Wiley Online Library (http://onlinelibrary.wiley.com/), has been retracted by agreement between the journal Editor-in-Chief, Robert Heath, and Wiley Periodicals LLC. Concerns were raised to the journal editorial office, as well as on PubPeer [1], regarding multiple duplicated images in the figures. Following investigation, evidence of duplication was found within Figure 2A; between Figure 2A of this article and Figure 2B of a different article by some of the same authors [Shu et al. 2017: https://doi.org/10.1038/s41598-017-07633-7]; and between Figure 4A of this article and Figure 3 of a different article by some of the same authors [Tian et al. 2017: https://doi.org/10.1038/cddis.2017.2]. The authors cooperated with the investigation and sent a proposed correction, but this was not considered sufficient to resolve the concerns. The editor has lost confidence in the results reported, and therefore, the article must be retracted. The authors disagree with the decision. Reference: [1] B. Tianmuensis, "Notch Activation Promotes Osteoblast Mineralization by Inhibition of Apoptosis," PubPeer, 2025, https://pubpeer.com/publications/0AC64BDE43F94128FC9819A85657DF.
Unveiling the VEGFR2-TTI1-mTORC1 Axis: A Crucial Pathway in Hypoxia-Induced Erythropoiesis.
Wang J, Xiao J, Li Z … +3 more , Ren D, Li X, Li C
J Cell Physiol · 2026 May · PMID 42152561 · Publisher ↗
Erythropoiesis is a meticulously regulated process influenced by a multitude of factors. Prior research has demonstrated that hypoxic conditions (5% O) facilitate erythroid differentiation. Nevertheless, although our pre...
Erythropoiesis is a meticulously regulated process influenced by a multitude of factors. Prior research has demonstrated that hypoxic conditions (5% O) facilitate erythroid differentiation. Nevertheless, although our preliminary data indicate the involvement of VEGF/VEGFR2 in this process, the precise regulatory mechanism in erythropoiesis under hypoxia remains inadequately understood. In this study, an in vitro model of inhibited erythroid differentiation was developed using CD34 hematopoietic stem cells treated with a VEGFR2-neutralizing antibody. Additionally, the signaling axis was modulated under hypoxia conditions employing the mTOR inhibitor rapamycin and TTI1-siRNA. The findings revealed that hypoxia significantly upregulated VEGF/VEGFR2 expression and promoted erythroid differentiation. Conversely, VEGFR2 inhibition resulted in a substantial decrease in erythroid surface markers and hemoglobin synthesis. Proteomics analysis suggested that TTI1 and mTOR are pivotal components of this signaling axis, with their suppression effectively impeding erythropoiesis. Under hypoxic conditions, VEGFR2 may regulate erythroid differentiation of CD34 cells through a mechanism involving the TTI1-mTORC1 signaling pathway.
Ginsenoside-Rh2 Alleviates Pyroptosis of Nucleus Pulposus Cells by Activating Autophagy via HIF-1α to Retard the Progression of Intervertebral Disc Degeneration.
Xuan J, Chen J, Liu H … +2 more , Chen Y, Zhang Z
J Cell Physiol · 2026 May · PMID 42116708 · Publisher ↗
In the pathogenesis of intervertebral disc degeneration (IVDD), nucleus pulposus (NP) cell dysfunction is a pivotal factor, specifically manifested as extracellular matrix degradation, impaired autophagy, and pyroptosis....
In the pathogenesis of intervertebral disc degeneration (IVDD), nucleus pulposus (NP) cell dysfunction is a pivotal factor, specifically manifested as extracellular matrix degradation, impaired autophagy, and pyroptosis. Ginsenoside-Rh2 (GRh2) possesses pharmacological activities, yet its role in IVDD remains unclear. This study used interleukin-1β (IL-1β) to mimic the pathological state of IVDD in vitro: GRh2 restored NP cell viability, alleviated extracellular matrix damage, repaired autophagic function, and inhibited pyroptosis. Through network pharmacology and molecular docking, HIF-1α was identified as a key functional pathway; blocking HIF-1α with BAY872243 completely abolished the aforementioned effects of GRh2. In rat IVDD models, GRh2 maintained disc structural stability and extracellular matrix homeostasis, while BAY872243 reversed this protective effect. In conclusion, GRh2 alleviates IVDD by activating autophagy mediated by HIF-1α, as well as inhibiting pyroptosis and extracellular matrix damage, making it a potential therapeutic agent for IVDD.
Cell Mechanics in Cancer: Integrating Mechanotransduction Pathways Within the Tumor Microenvironment.
Sevgi M, Işık Y, Karaca C … +5 more , Çağlar E, Abdioğlu HB, Zendel F, Başbınar Y, Üvet H
J Cell Physiol · 2026 May · PMID 42112985 · Full text
Single-cell mechanical properties such as stiffness, elasticity, and viscosity, are crucial in governing biological processes like migration, proliferation, and differentiation. In cancer, the mechanical properties of ce...
Single-cell mechanical properties such as stiffness, elasticity, and viscosity, are crucial in governing biological processes like migration, proliferation, and differentiation. In cancer, the mechanical properties of cells undergo significant alterations, which contribute to tumor growth, metastasis, and resistance to therapy. This review focuses on cancer cell stiffness and explores how its regulation is disrupted by the complex interplay among cytoskeletal remodeling, nuclear mechanics, and extracellular matrix (ECM) interactions. Cancer-associated fibroblasts (CAFs) and ECM composition within the tumor microenvironment (TME) modulate cellular mechanics via mechanotransduction pathways involving Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) and integrin-focal adhesion kinase (FAK) signaling. Increasing evidence supports cell stiffness as a promising diagnostic and prognostic biomarker, as well as a predictor of treatment response. Therefore, advanced techniques for measuring cell stiffness such as atomic force microscopy (AFM), Brillouin microscopy, and acousto-holography are evaluated with a focus on their potential clinical applicability. However, translation into routine oncology practice remains limited by technical variability, lack of standardized protocols, and the need for large-scale clinical validation. This review highlights the potential of integrating biomechanical markers into clinical workflows as a means to advance cancer diagnostics and enable more personalized therapeutic strategies.
Progranulin and Inflammation-Induced Cancer: An Important Player in the Tumor Microenvironment?
Insinga G, Tomassetti C, Satasiya V … +4 more , Gimigliano F, Giordano A, Giurisato E, Morrione A
J Cell Physiol · 2026 May · PMID 42112954 · Publisher ↗
Progranulin (PGRN) is a multifunctional glycoprotein recognized as a key regulator at the intersection of tumor progression and inflammation. Originally described as a mitogenicgrowth factor within the tumor. PGRN is now...
Progranulin (PGRN) is a multifunctional glycoprotein recognized as a key regulator at the intersection of tumor progression and inflammation. Originally described as a mitogenicgrowth factor within the tumor. PGRN is now known to exert a broad spectrum of biological effects within the tumor microenvironment (TME), where it functions as both an oncogenic driver and an immunomodulatory molecule. Beyond its capacity to promote tumor cell proliferation, migration, and epithelial-mesenchymal transition (EMT). PGRN critically shapes the inflammatory and stromal landscape that sustains tumor growth. This review aims to comprehensively summarize current knowledge on the multifaceted roles of PGRN within the TME, with a particular focus on its functions in immune and stromal cells that contribute to tumor progression and immune evasion. In fact, it reprograms TME toward an immunosuppressive state by activating signaling pathways such as TNFR2/STAT3 and PI3K/AKT. It promotes M2-like macrophage polarization, enhances PD-L1 expression, supports regulatory T-cell stability, and suppresses CD8⁺ T- and NK-cell cytotoxicity, and fosters immune evasion. Simultaneously, PGRN affects stromal components by activating cancer-associated fibroblasts (CAFs), remodeling the extracellular matrix, and stimulating angiogenesis. These coordinated actions position PGRN as a central orchestrator of tumor-associated inflammation. Despite these insights, its roles in myeloid-derived suppressor cells, neutrophils, and other stromal subsets remain poorly understood. Therefore, investigating PGRN's influence on these cells is crucial for understanding tumor progression and therapeutic resistance and may reveal novel strategies to disrupt PGRN-dependent inflammatory circuits and enhance anti-tumor immunity.
Decoding the Hexosamine Biosynthesis Pathway: Implications for Novel Therapeutic Strategies in Sarcoma.
Rahimizadeh P, Miallot R, De Bellis C … +2 more , Jolivet P, Przybyl J
J Cell Physiol · 2026 May · PMID 42112659 · Full text
Cancer cells rewire their metabolism to sustain a high proliferation rate. Sensing external cues is essential to match the metabolic fluxes of the cells to the external stimuli. As part of the glucose metabolism, the hex...
Cancer cells rewire their metabolism to sustain a high proliferation rate. Sensing external cues is essential to match the metabolic fluxes of the cells to the external stimuli. As part of the glucose metabolism, the hexosamine biosynthesis pathway (HBP) is considered a nutrient-sensing pathway. The HBP produces UDP-GlcNAc, a key precursor for N-linked glycosylation, O-linked glycosylation, and O-GlcNAcylation. These post-translational modifications can influence protein folding, interactions, and subcellular localization. Altered glycosylation of oncogenic proteins has been linked to the acquisition of malignant properties. In this review, we outline the current knowledge of molecular alterations and the prognostic role of the expression of HBP enzymes in sarcoma. We catalog the known sites of N-/O-linked glycosylation and O-GlcNAc modifications in molecular drivers of mesenchymal tumors, and discuss the potential effect of these modifications on protein function. We also summarize the studies that examined the effect of the HBP inhibitors in preclinical models of cancer, and explore the potential of the HBP inhibition as a novel therapeutic approach for sarcoma. Finally, we present recent progress in drug development for targeting the HBP, and delineate the key technological innovations needed to accelerate the preclinical and clinical research on pharmacological inhibition of the HBP.
Connexin Regulation and Modulation of Neural Stem Cell Differentiation Induced by Cell-Permeable Itaconate.
Denaro S, Spina SR, D'Aprile S … +6 more , Gervasi A, Torrisi F, Parenti C, Zappalà A, Vicario N, Parenti R
J Cell Physiol · 2026 May · PMID 42112596 · Full text
Neural stem cells (NSCs) are multipotent cells of the central nervous system (CNS) capable of self-renewal, differentiation, and responding to and shaping the surrounding microenvironment. Their continuous crosstalk with...
Neural stem cells (NSCs) are multipotent cells of the central nervous system (CNS) capable of self-renewal, differentiation, and responding to and shaping the surrounding microenvironment. Their continuous crosstalk with surrounding CNS cells is a key component of their therapeutic potential, particularly in tissue repair and regeneration. Communication in the CNS relies on complementary mechanisms, including connexins (Cxs)-based intercellular communication, to maintain homeostasis and coordinate responses to physiological and pathological stimuli. Itaconate, an endogenous shunt product of the tricarboxylic acid cycle, functions as an immunometabolite involved in inflammation and oxidative stress and has recently been implicated in neuroimmune modulation. Although itaconate influences several signalling cascades and is exchanged between cells and/or released into the extracellular milieu, its effects on Cxs expression in NSCs and whether the modulation of Cxs expression profile represents a driving factor in shaping cell fate remain unclear. Here, we investigated the effect of dimethyl itaconate, a cell-permeable esterified itaconate derivative, on the expression profile of Cxs in NSCs and its potential to modulate NSCs fate and differentiation. We found that dimethyl itaconate modulates Cxs expression in NSCs, increasing Cx36 levels, and promotes NSCs differentiation toward a neuronal phenotype, while inhibition of Cxs-based channels with carbenoxolone or mefloquine abolishes these dimethyl itaconate-induced effects. Collectively, these findings highlight a regulatory role for cell-permeable itaconate and contribute to the understanding of intercellular communication in the CNS microenvironment, providing insights into potential therapeutic strategies for CNS repair and regeneration.
Cell Membrane Biogenesis: A Matter of Survival. Its Role in Renal Epithelia Restitution After Calcium Oxalate Injury.
Parra LG, Sendyk DE, Verstraeten SV … +5 more , Salafia AF, Favale NO, Gómez EM, Tome MDCF, Casali CI
J Cell Physiol · 2026 May · PMID 42093332 · Publisher ↗
Calcium oxalate (CaOx) is the main component of kidney stones. These stones interact with the surface of renal epithelial cells and initiate injury. In differentiated renal epithelial cells (DREC), we demonstrated that o...
Calcium oxalate (CaOx) is the main component of kidney stones. These stones interact with the surface of renal epithelial cells and initiate injury. In differentiated renal epithelial cells (DREC), we demonstrated that oxalate (Oxa) injures monolayers, which undergo a type II epithelial-mesenchymal transition during the first 24 h (the damage period). Thereafter, cells gradually recover their morphology, restituting the monolayer between 48 and 72 h (the restitution period). Since Oxa induces lipid peroxidation (LPO), which disrupts membrane homeostasis, we hypothesize that epithelial restitution occurs after the activation of lipid metabolism and the restoration of cellular membrane integrity. The goal of this study was to determine the role of glycerolipid (GL) metabolism in DREC monolayer survival and restitution after Oxa injury. DREC monolayers were incubated with 1.5 mM Oxa during the damage and the restitution periods. After the damage period, we found alterations in the DREC monolayer and a decrease in cell number. Moreover, Oxa-induced LPO changes membrane composition and properties. These changes were accompanied by the activation of glycerophospholipid (GP) and triacylglyceride (TG) synthesis and by an increase in the number of lipid droplets (LD), but a decrease in their size. The inhibition of lipin activity impaired GP and TG synthesis, completely preventing DREC monolayer restitution. Collectively, these results demonstrate that Oxa-induced LPO disrupts DREC membrane properties, changing their biophysics and composition, which affects cell physiology. To restore cell homeostasis, GL synthesis and LD biogenesis are activated, allowing the gradual recovery of the DREC monolayer phenotype, and highlighting the importance of membrane structure maintenance in cell survival.
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