International Journal Of Biological Sciences[JOURNAL]
Sun
200 papers
Esophageal Small Cell Carcinoma: From Bench Discoveries to Bedside Therapeutics.
Wang Z, Zhang J, Ji C … +9 more , Yu J, Shen B, Meng X, Shan Z, Guan L, Yue B, Xin D, Zhao T, Wang F
Int J Biol Sci · 2026 · PMID 42328440 · Full text
Small cell carcinoma of the esophagus (SCCE) is both rare and aggressive. Lacking its own guidelines, it has historically been managed with treatment models borrowed from small cell lung cancer (SCLC). However, advances...
Small cell carcinoma of the esophagus (SCCE) is both rare and aggressive. Lacking its own guidelines, it has historically been managed with treatment models borrowed from small cell lung cancer (SCLC). However, advances in multi-omics and immunology are beginning to uncover distinct molecular and immune features in SCCE. These include frequent alterations in NOTCH1 and PTEN, ASCL1 and NEUROD1 transcriptional programs, and a highly adaptive immunosuppressive tumor microenvironment. Together, they point to unique biological traits that may be targetable. Clinically, conventional chemotherapy, radiotherapy, and surgery are being reassessed, with neoadjuvant therapy showing increasing value. Mechanism-driven strategies such as anti-angiogenic and DLL3-targeted therapies are under active exploration. At the same time, emerging biomarkers and multimodal predictive models are offering new tools for risk stratification and personalized management. Yet pathology adds further challenges: boundaries between SCCE, squamous cell or adenocarcinomas with neuroendocrine differentiation, and mixed or collision tumors remain blurred, creating diagnostic and therapeutic uncertainty. These challenges highlight an important shift-SCCE is no longer a clinical "black box" but rather a frontier that demands resolution through a translational lens. By realigning fragmented basic research with clinical evidence, this review not only presents a comprehensive picture of SCCE but also aims to provide clear therapeutic direction for this malignancy.
WDR82 suppresses breast cancer progression by inhibiting ERK-driven chemokine expression and neutrophil infiltration.
Yu Q, Yang J, Lu F … +9 more , Liu W, Han Z, Bao Y, Xu X, Xu J, Gao W, Cong B, Chai Y, Cao X
Int J Biol Sci · 2026 · PMID 42328439 · Full text
Elucidating tumor-intrinsic mechanisms orchestrating immunosuppressive tumor microenvironment (TME) and cancer immunoevasion is essential for overcoming cancer immunotherapy resistance and developing novel therapeutic st...
Elucidating tumor-intrinsic mechanisms orchestrating immunosuppressive tumor microenvironment (TME) and cancer immunoevasion is essential for overcoming cancer immunotherapy resistance and developing novel therapeutic strategies. WDR82, a member of the WD-40 protein family, exhibits context-dependent regulation of cancer with undefined role in breast cancer and immunosuppressive TME. Here we identify WDR82 as a critical tumor suppressor governing immune surveillance by restraining the ERK-chemokine-neutrophil axis. WDR82 expression is downregulated in human breast cancer and correlates with poor prognosis. Although WDR82 promotes tumor cell proliferation , it suppresses tumor growth exclusively in immunocompetent hosts by enhancing neutrophil infiltration and CD8⁺ T cell exhaustion, creating an immunosuppressive TME. Neutrophil depletion abolishes WDR82's tumor-suppressive effect, confirming the functional dependency on this axis. Mechanistically, WDR82 directly binds MEK1/2 to disassemble c-RAF-MEK binding and inactivate ERK signaling. deletion restores ERK-dependent tumor cell CXCL2 and CXCL7 production to promote CXCR2-mediated neutrophil recruitment in the TME. Importantly, intratumoral WDR82-expressing adenovirus delivery reverses neutrophil accumulation and T cell exhaustion, suppressing tumor progression. Our findings uncover a previously unrecognized mechanism by which WDR82 suppresses MEK-ERK signaling, ERK-dependent chemokines production and neutrophil infiltration, consequently relieving immunosuppressive TME. This work establishes a promising therapeutic strategy for breast cancer.
Targeting QRICH1 suppresses epithelial-mesenchymal transition and tumor growth in liver cancer through the Connexin43/USP1 mediated Snail1 stabilization.
Park SY, Shim BS, Kim B … +1 more , Kim SH
Int J Biol Sci · 2026 · PMID 42328438 · Full text
Although glutamine-rich protein 1 (QRICH1) has been implicated in endoplasmic reticulum stress-associated epithelial-mesenchymal transition (EMT), its mechanistic role in liver cancer progression remains unclear. QRICH1...
Although glutamine-rich protein 1 (QRICH1) has been implicated in endoplasmic reticulum stress-associated epithelial-mesenchymal transition (EMT), its mechanistic role in liver cancer progression remains unclear. QRICH1 expression was analyzed in public datasets and clinical liver cancer specimens. Gain- and loss-of-function approaches were performed to assess proliferation, migration, invasion, and EMT signaling , and tumorigenicity was evaluated using a xenograft mouse model. QRICH1 was significantly overexpressed in liver cancer tissues with poor clinical outcomes. QRICH1 silencing markedly suppressed cell proliferation, migration, invasion, and EMT, accompanied by decreased Snail1 and ZEB1 expression and restoration of Connexin43 (GJB1). Co-immunoprecipitation and immunofluorescence analyses demonstrated that QRICH1 physically interacted and colocalized with Snail1 and USP1. Molecular docking further supported stable binding interfaces among these proteins. Ubiquitination and cycloheximide chase assays revealed that QRICH1 enhanced Snail1 protein stability through USP1-mediated deubiquitination. Functionally, QRICH1 suppressed gap junction intercellular communication, consistent with reduced Connexin43 expression, but not Connexin26 and Connexin32. , QRICH1 knockdown significantly inhibited tumor growth and reduced the expression of USP1, Snail1, PCNA, VEGF, and N-cadherin, while increasing E-cadherin and Connexin43. Collectively, these findings identify QRICH1 as a key oncogenic regulator that promotes liver cancer progression by stabilizing Snail1 via USP1-dependent deubiquitination and disrupting Connexin43-mediated gap junction signaling.
Unveiling Interleukin-40: A Novel Regulator of Macrophage and B Cell Function in Allergic Asthma.
Li A, Wong KC, Huang D … +7 more , Chen F, Li H, Gao X, Leung TF, Wong GW, Ko WH, Wong CK
Int J Biol Sci · 2026 · PMID 42328437 · Full text
Allergic asthma is characterized by chronic airway inflammation and heightened type 2 immune responses. Although inhaled corticosteroids are the mainstay of therapy, a subset of patients exhibits suboptimal responses, un...
Allergic asthma is characterized by chronic airway inflammation and heightened type 2 immune responses. Although inhaled corticosteroids are the mainstay of therapy, a subset of patients exhibits suboptimal responses, underscoring the need for new therapeutic targets. In this study, we investigated the role of novel B cell-related interleukin-40 (IL-40) in allergic asthma using patient samples and a house dust mite (HDM)-induced mouse model. Through transcriptomic and immunological profiling, our findings revealed that IL-40 expression was significantly upregulated in both patients with allergic asthma and murine model. Elevated IL-40 levels exacerbated airway hyperresponsiveness (AHR), promoted inflammatory cell infiltration, and increased the production of type 2 cytokines, indicating a key role in amplifying allergic airway inflammation. Importantly, treatment with a neutralizing antibody against IL-40 or genetic deletion of IL-40 significantly alleviated airway inflammation, suggesting its therapeutic potential. Mechanistically, these pro-inflammatory effects of IL-40 were closely associated with alterations in macrophage polarization and B cell development. Macrophages exhibited the highest induction of IL-40 secretion following allergen exposure and responded most strongly to IL-40 stimulation. This response involved the activation of the JAK/STAT1 and p38-MAPK signaling pathways, driving their polarization toward a pro-inflammatory phenotype while inhibiting the differentiation of a specific Arg1 macrophage subset. Although T cells did not display a direct response to IL-40 stimulation, IL-40 was found to be essential for normal B cell development. IL-40 mice showed a marked reduction in pre-B cells in the bone marrow and impaired B cell maturation in the spleen, characterized by decreased follicular B cell populations. Genes involved in B cell receptor synthesis and complement activation were notably downregulated in IL-40 mice. These findings position IL-40 as a key regulator of allergic asthma pathogenesis and suggest its potential as a novel biomarker and therapeutic target for airway inflammation.
RNA variation as the driver of genomic efficiency and phenotypic complexity.
Jiang Z, van Rooyen M, Michal JJ … +5 more , Khaerunnisa I, Anwar S, Fu X, Yang J, Miller SP
Int J Biol Sci · 2026 · PMID 42328436 · Full text
Despite decades of genome sequencing and annotation, a fundamental paradox remains unresolved: how organisms with finite and relatively stable gene numbers generate extraordinary phenotypic diversity. In this review, we...
Despite decades of genome sequencing and annotation, a fundamental paradox remains unresolved: how organisms with finite and relatively stable gene numbers generate extraordinary phenotypic diversity. In this review, we propose that regulated RNA variant diversity provides a critical level of resolution for understanding genome expression, which we describe as a conceptual "minimal functional unit" for distinguishing distinct regulatory or functional outcomes. We synthesize evidence that transcript diversity arises through hierarchical and combinatorial RNA variation operating at three levels. At the genome level, diverse gene biotypes-including protein-coding genes, non-coding RNAs, pseudogenes, transposable elements, and bifunctional loci-expand regulatory capacity beyond classical gene definitions. At the gene level, alternative transcription initiation, splicing, and polyadenylation generate structurally and functionally distinct transcript isoforms. At the transcript level, RNA editing and chemical RNA modifications further modulate RNA stability, localization, translation, and immune recognition, forming a dynamic epitranscriptome. Together, these layers of RNA variation dramatically amplify functional output without increasing gene number, providing a coherent framework for linking static genomes to dynamic phenomes. By integrating conceptual models and biological examples, this review highlights RNA variation as a central organizing principle in genetics, with broad implications for evolution, development, and disease.
CD109 Drives Stemness and Chemoresistance in Colorectal Cancer via LRRC8A/AKAP12/PKCα-Mediated STAT3 Activation and WNT Signaling.
Bartolomé RA, Calvo-López T, Otero-Núñez P … +14 more , Estaras M, Fernández-Barral A, Barbáchano A, Boukich I, Cuerda-López M, Fernández-Aceñero MJ, Rodríguez-Urquirizar G, Mariscal-Casero A, Padilla-Blanco M, Montoya M, O'Loghlen A, Fernández-Fernández JM, Gonzalez-Sancho JM, Casal JI
Int J Biol Sci · 2026 · PMID 42328435 · Full text
Colorectal cancer (CRC) is the third most prevalent type of cancer worldwide, with a poor survival rate at the metastatic stage. Here, we identify CD109-a negative regulator of TGFβ signaling-as a key driver of stemness...
Colorectal cancer (CRC) is the third most prevalent type of cancer worldwide, with a poor survival rate at the metastatic stage. Here, we identify CD109-a negative regulator of TGFβ signaling-as a key driver of stemness and drug resistance through modulation of Wnt signaling in advanced CRC. CD109 expression strongly correlates with TGFβ levels in patient tumors and is enriched in the aggressive CRIS-B subtype, where it associates with poor clinical outcome. CD109 silencing reduced STAT3 phosphorylation and cell proliferation, without affecting migration or invasion. Moreover, global expression analysis revealed downregulation of various hallmarks of cancer stemness (i.e. LGR5 expression), together with increased TGFβ signaling and cellular senescence. Mechanistically, CD109 interacts with LRRC8A, a subunit of the volume-regulated anion channel (VRAC), which associates with AKAP12 to activate PKCα and promote STAT3 phosphorylation. This CD109/LRRC8A/AKAP12/PKCα axis sustains Wnt signaling, stemness, and drug resistance. Consistently, co-expression of CD109/LRRC8A/AKAP12 correlates with poor prognosis in CRC patients. Genetic or pharmacological disruption of this CD109/LRRC8A/AKAP12/PKCα axis impaired STAT3 signaling, reduced LGR5 expression and Wnt signaling, and sensitized cells to chemotherapy. , CD109 or LRRC8A knockdown significantly impaired liver homing and metastatic colonization in mouse models, showing stronger effects in Swiss nude mice than in highly immunodeficient NSG mice. Collectively, these findings support CD109 as a central regulator for STAT3-driven stemness and chemoresistance in advanced CRC, via the LRRC8A/AKAP12/PKCα axis, and highlight its potential value as a therapeutic target in metastatic disease.
H3K18la-PSMG1 Axis in Bladder Cancer Progression: Curcumin as a Therapeutic Candidate.
Yu Z, Zhang J, Wang Z … +10 more , Wei S, Chen C, Huang Y, Fan Q, Deng F, Chen H, Zhong Z, Hou L, Tan W, Li F
Int J Biol Sci · 2026 · PMID 42328434 · Full text
Although multiple therapeutic modalities, including surgery, chemotherapy, radiotherapy, immunotherapy, and targeted therapy, have improved the management of bladder cancer, the clinical outcome of muscle-invasive bladde...
Although multiple therapeutic modalities, including surgery, chemotherapy, radiotherapy, immunotherapy, and targeted therapy, have improved the management of bladder cancer, the clinical outcome of muscle-invasive bladder cancer (MIBC) remains unsatisfactory. To address this challenge, we identified MIBC-related genes (MIBC.RGs) through transcriptomic and proteomic analyses and developed a prognostic model to predict patient outcomes. Among the candidate genes, PSMG1 was prioritized through an integrated framework combining machine learning-based screening and single-cell transcriptomic analysis. Experimental analyses revealed that PSMG1 was markedly upregulated in bladder cancer (BCa), progressively upregulated from normal tissue to MIBC, and PSMG1 silencing reduced cell proliferation, invasion, and clonogenic capacity in vitro, while attenuating tumor growth in vivo. Mechanistically, our data suggest that PSMG1 may promote BCa aggressiveness, at least in part, by affecting E-cadherin stability and EMT-related signaling. Epigenetic profiling revealed significant H3K18la enrichment at the PSMG1 promoter, supporting a potential H3K18la-PSMG1 regulatory axis. Finally, molecular docking, proteomic profiling, and Drug Affinity Responsive Target Stability (DARTS) assays prioritized Curcumin as a candidate compound potentially associated with PSMG1 targeting. Overall, our findings indicate that the H3K18la-PSMG1 axis may participate in BCa progression and support further evaluation of Curcumin in PSMG1-associated therapeutic strategies.
USP33 Promotes Lung Adenocarcinoma Brain Metastasis by Inhibiting the K48-Linked Ubiquitination and Degradation of S100A9 and Facilitating Vimentin Secretion.
Wang Z, Chang M, Wang Y … +7 more , Qu Y, Wu W, Liu J, Guo X, Zhou Y, Ma W, Wang Y
Int J Biol Sci · 2026 · PMID 42328433 · Full text
Brain metastasis has a deterministic influence on the evolutionary trajectory of lung adenocarcinoma (LUAD). Given the profound clinical importance of LUAD brain metastases and the formidable obstacles that hinder their...
Brain metastasis has a deterministic influence on the evolutionary trajectory of lung adenocarcinoma (LUAD). Given the profound clinical importance of LUAD brain metastases and the formidable obstacles that hinder their precise prediction, novel therapeutic targets are urgently needed. Notably, a substantial fraction of lung carcinoma cells in brain metastatic foci demonstrates marked S100A9 overexpression. However, whether these cells represent the primary drivers of brain metastasis requires further elucidation. Coculture of S100A9-overexpressing LUAD cells with human brain microvascular endothelial cells (HBMECs) markedly suppressed the expression of the tight junction components ZO-1, Occludin, and Claudin-5 within the endothelial barrier. These cocultured HBMECs also exhibited compromised angiogenic potential, elevated levels of reactive oxygen species, and increased endothelial-to-mesenchymal transition. Additionally, these cells displayed attenuated proliferative and migratory capacities and mitochondrial membrane potential depolarization along with increased autophagy characterized by increased lysosomal acidification. Conversely, LUAD cells with elevated S100A9 expression exhibited increased proliferative, migratory, and invasive capacities and increased tumorigenicity and potential for brain metastasis. In LUAD cell lines, USP33 stabilizes S100A9 via K48-linked deubiquitination, which promotes the expression and extracellular secretion of vimentin. LUAD cells reduce blood‒brain barrier integrity, increase permeability, and disrupt the intra- and extracellular functions of HBMECs, thus promoting parenchymal infiltration and the establishment of metastatic lesions.
Fibrillin-1 Orchestrates a Pro-senescent Niche Driving Peritubular Endothelial Senescence via ZEB1/endothelin-1/β-catenin Signaling.
Huang J, Zhang X, Yao Z … +6 more , Zhang Y, Huang D, Liu Y, Hou FF, Liu Y, Li L
Int J Biol Sci · 2026 · PMID 42328432 · Full text
Microvascular rarefaction is a predominant pathological hallmark of chronic kidney disease (CKD), functioning simultaneously as a catalyst and consequence of progressive renal compromise. Although endothelial senescence...
Microvascular rarefaction is a predominant pathological hallmark of chronic kidney disease (CKD), functioning simultaneously as a catalyst and consequence of progressive renal compromise. Although endothelial senescence constitutes a cardinal mediator of microvascular attrition in CKD, its upstream regulatory mechanism remains elusive. Here, using integrated single-cell/spatial transcriptomics, decellularized scaffold modeling, diverse murine CKD models, vascular ultrasonography, and tissue-clearing-enabled 3D imaging, we identify fibrillin-1 (FBN1), a core constituent of the fibrogenic niche, as an architect of a pro-senescent microenvironment that directly triggers endothelial senescence. Mechanistically, FBN1 upregulates the transcription factor ZEB1, which binds to the promoter to enhance endothelin-1 (ET-1) transcription, thereby activating the ET-1/β-catenin signaling axis to execute cellular senescence. This cascade is abolished by knockdown, ET-1 receptor antagonism, or β-catenin inhibition. Importantly, tubule-specific deletion suppresses endothelial senescence, attenuates capillary rarefaction, and ameliorates renal function across CKD models. Our study unveils the FBN1/ZEB1/ET-1/β-catenin axis as a spatially organized signaling pathway linking to endothelial senescence, demonstrating how matrix-embedded components actively perpetuate pathogenesis by orchestrating stable pathological microenvironments. These findings provide a conceptual framework for CKD-associated vascular deterioration and highlight microenvironmental reprogramming as a therapeutic paradigm.
Role of WDR66 in Stemness, Therapy Resistance and Tumor microenvironment modulation in Head and Neck Cancer.
Sanchez-Diaz L, Espinosa-Sánchez A, Carnero A
Int J Biol Sci · 2026 · PMID 42328431 · Full text
Head and neck cancer comprises a variety of malignant tumors affecting regions such as the oral cavity, pharynx, larynx, paranasal sinuses, nasal cavity and salivary glands. These tumors are highly heterogeneous, making...
Head and neck cancer comprises a variety of malignant tumors affecting regions such as the oral cavity, pharynx, larynx, paranasal sinuses, nasal cavity and salivary glands. These tumors are highly heterogeneous, making it difficult to identify specific biomarkers and effective treatments, increasing mortality and recurrence rates. Databases analyzed to identify genes with altered expression in tumor tissue showed WDR66 able predict prognosis and survival, in HNSCC, but whose involvement in tumorigenesis is unknown. High WDR66 expression was associated with a worse prognosis, although its overexpression did not significantly alter basic tumor properties in cancer cells or . However, we observed an increase in pluripotency factors (OCT3/4, SOX2, KLF4, LIN28), resistance to chemotherapies and a decrease in apoptosis. Consistently, decreasing WDR66 expression using CRISPR showed a reduction in tumorsphere formation, lower expression of pluripotency-related genes, decreased cell migration, and increased sensitivity to cisplatin. These effects were more pronounced , suggesting a relevant role of WDR66 in the tumor microenvironment. The medium conditioned by cells overexpressing WDR66 promoted migration, maintained the stem cell phenotype, and inhibited immune differentiation, harboring soluble factors involved in progression and metastasis. In this media, we identified several cytokines and growth factors related to inflammation and immune system modulation. In conclusion, WDR66 emerges as a potential biomarker of poor prognosis and a possible predictor of response to immunotherapy, given its impact on cellular pluripotency, treatment resistance and modification of the tumor microenvironment in head and neck cancer.
SREBP2-activated CNPY3 Phase Separation Promotes Colorectal Cancer by Enhancing MDM2-mediated p53 Degradation.
Li X, Yin MY, Wei YF … +5 more , Xing J, Zhang Q, Zong Y, Zhang ST, Xie SA
Int J Biol Sci · 2026 · PMID 42212339 · Full text
Dysregulated cholesterol metabolism is a recognized metabolic hallmark of cancer. While the transcription factor SREBP2 is a master regulator of this pathway, how its activation converts metabolic stress into the develop...
Dysregulated cholesterol metabolism is a recognized metabolic hallmark of cancer. While the transcription factor SREBP2 is a master regulator of this pathway, how its activation converts metabolic stress into the development of carcinogenic signals in colorectal cancer (CRC) remains unclear. Through clinical and preclinical analyses, we first confirmed that hypercholesterolemia and elevated tumoral SREBP2 are hallmarks of CRC. Using multi-omics integration, we identified CNPY3 as a direct transcriptional target of SREBP2. Functionally, CNPY3 drives CRC cell proliferation, invasion, and tumor growth via a cholesterol synthesis-independent oncogenic program. Clinically, high CNPY3 expression robustly correlated with advanced disease and poor patient survival. Mechanistically, we discovered that CNPY3 undergoes liquid-liquid phase separation (LLPS), a property dependent on its intrinsically disordered C-terminal region. This LLPS capacity is essential for its oncogenic function, as it enables CNPY3 to enhance MDM2 phosphorylation at the activating Ser166 site and promote its nuclear translocation. Consequently, CNPY3 potentiates MDM2-mediated ubiquitination and degradation of the tumor suppressor p53. Genetic ablation of p53 completely abolished the pro-tumorigenic effects of CNPY3, confirming p53 as the critical downstream effector. Crucially, this axis specifically targets wild-type p53, having no effect on common p53 mutants. Pharmacological disruption of the MDM2-p53 interaction with Nutlin-3 effectively reversed CNPY3-driven malignancy both and . Our work unveils a SREBP2-CNPY3-MDM2-p53 signaling axis that links cholesterol metabolic dysregulation to p53 pathway inactivation in CRC. We further established that the oncogenic activity of CNPY3 is mediated through its biophysical property of LLPS. These findings nominate CNPY3 as a novel prognostic biomarker and a compelling therapeutic target for p53-wild-type CRC.
Alpha-ketoglutarate Potentiates IL-1β Production and Suppressive Mechanisms of Myeloid-Derived Suppressor Cells by Altering Redox Metabolism and Inducing Autophagy.
Milanović M, Pavlović L, Bekić M … +5 more , Đokić J, Stojadinović M, Radojević D, Čolić M, Tomić S
Int J Biol Sci · 2026 · PMID 42212338 · Full text
Alpha-ketoglutarate (αKG) has shown promise in cancer immunotherapy due to its profound impact on cancer cell metabolism and gene expression. However, its effects on myeloid-derived suppressor cells (MDSCs), critical imm...
Alpha-ketoglutarate (αKG) has shown promise in cancer immunotherapy due to its profound impact on cancer cell metabolism and gene expression. However, its effects on myeloid-derived suppressor cells (MDSCs), critical immunosuppressive components of the tumour microenvironment, remain poorly understood. Using a model of GM-CSF/IL-6-induced monocyte-derived (mo)MDSCs we found that non-toxic doses of non-esterified αKG expanded CD14HLA-DR moMDSCs, unlike esterified dimethyl-αKG. The αKG-moMDSCs displayed an enhanced suppressive phenotype, upregulated ILT-4 and IL-10, and showed an increased capacity to suppress Th1 cells. However, αKG-moMDSCs exhibited a heightened IL-1β production upon LPS stimulation, promoting Th17 cell expansion. This pro-inflammatory effect was consistent with oxoglutarate receptor (OXGR1)-dependent ROS increase, reduced Erk1/2 and Akt phosphorylation, reduced NRF-2 nuclear translocation and altered oxidative phosphorylation, as it could be mitigated by OXGR1-specific small interfering (si)RNAs delivered via lipid nanoparticles. Notably, the enhanced capacity of αKG-moMDSCs to suppress T cell proliferation and induce conventional FoxP3 regulatory T cells was independent of OXGR1, relying instead on Atg5-mediated increase in autophagy flux and IL-10 production. Atg5 was dispensable for ILT-4 upregulation, but still essential for the induction of FoxP3 type 1 and type 2 regulatory T (Tr1 and Tr2) cells, as well as OXGR1/ROS-mediated Th17 induction. Therefore, non-esterified αKG may promote moMDSC-mediated chronic inflammation and T cell dysregulation, potentially compromising its therapeutic efficacy in cancer immunotherapy.
Neutrophil Extracellular Traps in Pancreatic Ductal Adenocarcinoma: A Vicious Cycle in the Tumor Microenvironment and Targeted Interventions.
Zhao L, Yuan H, Chen Z … +3 more , Xia X, Tian X, Wang S
Int J Biol Sci · 2026 · PMID 42212337 · Full text
Neutrophil extracellular traps (NETs) are web-like structures released by activated neutrophils and initially identified for their role in antimicrobial defense. In recent years, growing evidence has demonstrated that NE...
Neutrophil extracellular traps (NETs) are web-like structures released by activated neutrophils and initially identified for their role in antimicrobial defense. In recent years, growing evidence has demonstrated that NETs contribute to the development and progression of various malignancies. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive digestive-system cancer characterized by strong invasiveness and poor prognosis. Notably, substantial infiltration of NETs is frequently observed within the PDAC tumor microenvironment (TME). Clinical evidence indicates that this phenomenon is closely associated with metastatic progression and reduced patient survival. This review systematically elaborates how the PDAC TME recruits and activates neutrophils and induces NET formation through multiple pathways, including extracellular matrix (ECM) signaling, cell-cell interactions, cytokine secretion, and epigenetic dysregulation. In addition, it examines the mechanisms through which NETs, functioning as a regulatory hub, facilitate PDAC progression by inducing angiogenesis, altering the stromal structure, driving tumor cell proliferation and invasion, and creating an immunosuppressive environment. Finally, we summarize the latest therapeutic strategies targeting NETs in PDAC and provide an outlook on future research directions in this field.
Endothelial Klf9 fine-tunes Akt signaling to act as a transcriptional brake restraining retinal angiogenesis.
Wu H, Yang T, Xun Y … +6 more , Zhou M, Zhang Y, Yao X, Chang Y, Lei Y, Yan H
Int J Biol Sci · 2026 · PMID 42212336 · Full text
Retinal angiogenesis requires precise transcriptional regulation. Krüppel-like factor 9 (Klf9) has been implicated in various biological processes; however, its specific role in retinal vascular development and ocular ne...
Retinal angiogenesis requires precise transcriptional regulation. Krüppel-like factor 9 (Klf9) has been implicated in various biological processes; however, its specific role in retinal vascular development and ocular neovascular disease remains unclear. In this study, we identified Klf9 as a critical transcriptional regulator of retinal vascular homeostasis. Spatiotemporal transcriptomic and single-cell RNA sequencing analyses revealed that Klf9 was highly enriched in retinal endothelial cells and upregulated during vascular maturation. Using genetic mouse models, we demonstrated that endothelial-specific Klf9 deletion accelerated neonatal retinal vascular expansion and tip cell formation, whereas its overexpression delayed angiogenesis and disrupted barrier function. In oxygen-induced retinopathy, Klf9 loss exacerbated pathological neovascularization and leakage, while its overexpression conferred protection. Integrated RNA-seq and ATAC-seq profiling of human retinal microvascular endothelial cells revealed that Klf9 represses a network of genes involved in the PI3K-Akt pathway and focal adhesions. Key effectors, including , , and were suppressed by reduced chromatin accessibility at their promoters. Both and rescue experiments confirmed that Akt activation reverses vascular hypoplasia caused by Klf9 overexpression, whereas Akt inhibition normalizes the hyper-angiogenic phenotype of the Klf9-deficient endothelium. Collectively, these findings establish Klf9 as a transcriptional brake on retinal angiogenesis, acting through chromatin-mediated suppression of the PI3K-Akt pathway, and provide new mechanistic insights and potential therapeutic targets for pathological retinal angiogenesis.
VDR-Spermidine Axis Protects Against Age-Related Granulosa Cell Dysfunction and Follicular Decline via DNMTs-Mediated p53 Methylation.
Chen H, Geng Q, Wang Q … +10 more , Li Y, Shangguan L, Zhu Z, Zhang J, Wang S, Chen X, Shen S, Wen Y, Wang D, Wang Y
Int J Biol Sci · 2026 · PMID 42212335 · Full text
Ovarian aging, marked by a decline in follicle quantity and quality, is a complex process whose underlying mechanisms remain elusive. Here, we identify the vitamin D receptor (Vdr) as a key anti-aging transcription facto...
Ovarian aging, marked by a decline in follicle quantity and quality, is a complex process whose underlying mechanisms remain elusive. Here, we identify the vitamin D receptor (Vdr) as a key anti-aging transcription factor whose expression in granulosa cells (GCs) declines with age. Using GCs-specific knockout (cVKO) mice and a -knockout (VKO) human granulosa-like cell line, we demonstrate that loss of triggers GCs aging and disrupts ovarian function. Integrated transcriptomic and metabolomic analyses from VKO and WT cells revealed that loss downregulates the spermidine (SPD) biosynthesis by directly suppressing the transcription of ornithine decarboxylase (). This led to SPD depletion, which in turn inhibited DNA methyltransferase (DNMTs) activity, resulting in hypomethylation of the p53 promoter and activation of the p53/p21 pathway. Crucially, supplementation with either SPD or its upstream methyl donor S-adenosylmethionine (SAM) rescued cVKO and VKO cell aging, improved hormonal profiles and promoted follicular development in cVKO mice. Furthermore, both supplements effectively delayed ovarian aging and improved fertility in naturally aged mice. Our study unveils the Vdr-spermidine-DNMTs axis as a fundamental mechanism safeguarding against ovarian aging, highlighting SPD and SAM as promising therapeutic agents for age-related female infertility.
The function of TLR2 and the microbiome in macrophage-dependent dissemination of nontuberculous mycobacterial gut infection.
Liu L, Hu W, Spaink HP
Int J Biol Sci · 2026 · PMID 42212334 · Full text
BACKGROUND: Nontuberculous mycobacteria (NTM) infections are increasing in incidence and mortality worldwide, yet the determinants of early intestinal colonization and subsequent dissemination remain poorly defined. Usi...
BACKGROUND: Nontuberculous mycobacteria (NTM) infections are increasing in incidence and mortality worldwide, yet the determinants of early intestinal colonization and subsequent dissemination remain poorly defined. Using a zebrafish larval model, we studied dissemination of two NTM strains, subspecies (strain MAC 101) and (strain Mma20) through the gastrointestinal (GI) tract. We performed bacterial immersion experiments and gut microinjection with these pathogens using mutant and wild-type zebrafish larvae in both germ-free (GF) and microbiome-colonized conditions. This study for the first time shows the roles of Toll-like receptor 2 (TLR2) and the microbiome in orchestrating immune responses in NTM gut infection and dissemination. RESULTS: In wild-type microbiome-colonized larvae, MAC 101 predominantly localizes in the posterior gut, in contrast to an anterior-biased distribution for Mma20 after 2.5 days of immersion infection. Both MAC 101 and Mma20 disseminate to posterior body region after 2.5 days of immersion infection. Robotic gut microinjection confirms the protective roles of TLR2 and the microbiome against proliferation of MAC 101 and Mma20. Expression analysis of downstream genes indicate that patterns of TLR2-dependent gene regulation differ between the two NTM species and show that the presence or absence of the microbiome differentially influences specific transcriptional responses to infection. Macrophage ablation studies show that macrophages facilitate dissemination of gut bacteria to the posterior body region. Quantification of macrophages containing bacteria throughout the body show that the dissemination of bacteria by macrophages depends on TLR2, but not on the microbiome. Using the same approach, TLR2 chemical antagonist treatment confirms the results observed in mutant larvae. Live imaging of macrophage trajectories after bacterial gut microinjection show that macrophage motility after infection is impaired in mutant larvae compared to the wild type. Notably, the effect of TLR2 on macrophage motility differs between GF and microbiome-colonized conditions. CONCLUSIONS: TLR2 and the microbiome play critical roles in modulating host responses to MAC 101 and Mma20 gut infection. Our findings provide new insights into the coordinated roles of TLR2 signaling and the microbiome in controlling infection of mycobacteria via the gut and underscore the importance of TLR2 in macrophage function during mycobacterial gut infection and dissemination.
Plasticity-Driven Regeneration of Circumvallate Papilla After Lgr5+ Stem Cells Loss.
Baskaran SK, Adpaikar AA, Lee S … +9 more , Kim J, Lee YS, Jee J, Akutsu H, Porntaveetus T, Kim KW, Kim EJ, Lee JM, Jung HS
Int J Biol Sci · 2026 · PMID 42212333 · Full text
Taste receptor cells located within the papillae of the oral cavity have a defined lifespan of 8-12 days. They are continuously replenished by a pool of stem/progenitor cells residing outside the taste buds. Previous stu...
Taste receptor cells located within the papillae of the oral cavity have a defined lifespan of 8-12 days. They are continuously replenished by a pool of stem/progenitor cells residing outside the taste buds. Previous studies have identified Lgr5 positive stem/progenitor cells localized within the basal trench of the circumvallate papilla (CVP) as the source of all taste and non-taste epithelial cells. However, it remains unclear whether an alternative stem cell population within the CVP can regenerate the epithelium in the absence of Lgr5-expressing cells. Using Lgr5 mice in which Lgr5-expressing cells were selectively ablated via diphtheria toxin administration, we observed a substantial loss of these cells in the CVP, leading to rapid degeneration of taste buds, K8-expressing taste receptor cells, basal cells, and the basement membrane within 24 h post-injection. Notably, while the basal cells and basement membrane were fully regenerated at 72 h post-injection, taste buds reappeared at 2 weeks. Previous studies have demonstrated that SOX10-Cre-labeled cells originating from Von Ebner's gland (VEG) contribute to the CVP epithelium and are detected within the taste bud. However, the cellular dynamics and mechanistic role of these SOX10-Cre-labeled cells in the maintenance of taste buds remain unclear. Lineage tracing results revealed that K8/K14-expressing cells from the ducts of VEG contribute to the regeneration of taste buds, indicating that these duct-associated epithelial cells contribute to regeneration, potentially through injury-induced cellular plasticity in the absence of a resident Lgr5-expressing stem cell population.
Impaired redox adaptation through SLC38A5-dependent glutamine metabolism contributes to melatonin-mediated anoikis sensitivity and metastasis suppression in bone cancer.
Nguyen BT, Chen WC, Fong YC … +7 more , Ko CY, Chen HT, Hsu CJ, Huynh KT, Huang WC, Yang SF, Tang CH
Int J Biol Sci · 2026 · PMID 42212332 · Full text
Malignant bone cancer, primarily osteosarcoma and chondrosarcoma, are highly aggressive neoplasms originating from bone tissue and characterized by a strong propensity for lung metastasis. Tumor cells evade anoikis throu...
Malignant bone cancer, primarily osteosarcoma and chondrosarcoma, are highly aggressive neoplasms originating from bone tissue and characterized by a strong propensity for lung metastasis. Tumor cells evade anoikis through reactive oxygen species (ROS)-mediated redox homeostasis, which modulates signaling cascades that promote proliferation, survival, and metastatic invasion into distant sites. Melatonin, synthesized primarily by the pineal gland, has been implicated in cancer prevention and therapy due to its inhibitory effects on bone cancer growth and progression. Little is known about the mechanisms underlying anoikis resistance in bone cancer cells or whether melatonin can therapeutically modulate this process. We demonstrated that glutamine metabolism is essential for bone cancer cells to maintain anoikis resistance. Melatonin treatment disrupted glutamine metabolism and altered redox homeostasis, as evidenced by increased ROS accumulation and reduced NADPH/NADP⁺ ratios under anchorage-independent conditions. Notably, solute carrier family 38 member 5 (SLC38A5), a glutamine transporter, was identified as a critical regulator of bone cancer progression, with higher SLC38A5 expression correlating with poorer clinical outcomes. Melatonin suppressed SLC38A5 expression and attenuated anoikis resistance through inhibition of the PI3K-Akt signaling pathway. Consistently, reduced SLC38A5 expression was associated with decreased lung metastasis in melatonin-treated groups in an orthotopic mouse model. Collectively, our findings reveal a previously unrecognized role of melatonin in modulating glutamine-dependent redox balance and anoikis resistance in bone cancer. This study highlights SLC38A5-mediated glutamine metabolism as a critical determinant of metastatic potential and supports melatonin and SLC38A5 as promising therapeutic targets for osteosarcoma and chondrosarcoma.
Phase separation of p85β modulates hepatocellular carcinoma progression through POLR1A.
Zhang Y, Zhang D, Duan Y … +15 more , Cui G, Zhang Y, He B, Yao M, Li X, Chen C, Li Z, Yang S, Zheng J, Gu J, Zhang D, Liu Y, Lin Z, Hang H, Hao Y
Int J Biol Sci · 2026 · PMID 42212331 · Full text
PI3K complex consists of catalytic subunit p110s and regulatory subunit p85s. Emerging evidence indicates that p110-free p85 subunits play pivotal roles in diverse biological processes, including cancer progression. In t...
PI3K complex consists of catalytic subunit p110s and regulatory subunit p85s. Emerging evidence indicates that p110-free p85 subunits play pivotal roles in diverse biological processes, including cancer progression. In this study, we demonstrate the underlying mechanism of p110-free p85β in hepatocellular carcinoma (HCC) development. PIK3R2/p85β is upregulated in HCC and correlates with poor patient survival. Nuclear p85β, but not its cytoplasmic counterpart, exhibits oncogenic activity. In the nucleus of HCC cells, p85β undergoes liquid-liquid phase separation (LLPS) and specifically accumulates in the fibrillar centers of nucleoli, where it drives HCC progression. Within the nucleolar compartment, p85β interacts with and stabilizes POLR1A, the catalytic core subunit of RNA polymerase I, thereby enhancing rRNA biosynthesis and maintaining HCC stemness. Furthermore, we develop an engineered circular RNA that encodes a peptide containing p110α ABD domain, which effectively suppresses HCC tumor growth by simultaneously disrupting p85β/POLR1A condensates and inhibiting PI3K/AKT signaling pathway, offering a novel RNA-based therapeutic strategy against HCC.
Biomembrane-coated Nanoparticles Targeting circHIF1α Suppress Ovarian Cancer Metastasis and Cisplatin Resistance by Mediating System Xc⁻ Inactivation via SLC7A11/SLC3A2 to Induce Ferroptosis in Cancer Stem Cells.
Chang Y, Wang J, Ma L … +7 more , Liu Y, Zhu Y, Yi Y, Zhang D, Zhao Z, Sun L, Song Y
Int J Biol Sci · 2026 · PMID 42212330 · Full text
The hypoxic tumor microenvironment (TME) drives malignant progression by increasing the activity of cancer stem cells (CSCs), whose iron-dependent metabolism not only maintains their stemness but also promotes drug resis...
The hypoxic tumor microenvironment (TME) drives malignant progression by increasing the activity of cancer stem cells (CSCs), whose iron-dependent metabolism not only maintains their stemness but also promotes drug resistance and ferroptosis resistance by activating key signaling pathways. This study revealed that hypoxia induces circHIF1α expression in CSCs and that its expression is significantly associated with chemotherapy resistance in patients. Functional experiments confirmed that circHIF1α enhances CSC stemness by regulating iron metabolism and driving cancer progression. The mechanism involves the dual regulation of ferroptosis: binding SLC3A2 to block lysosomal degradation and sponging miR-375 to abrogate its inhibition of SLC7A11, synergistically activating system Xc⁻-mediated glutathione synthesis for ferroptosis resistance. Additionally, circHIF1α can be transferred between cells in the TME via exosomes, promoting iron metabolic reprogramming and the spread of drug resistance. Based on this mechanism, we developed a cell membrane-coated siRNA nanodelivery system targeting circHIF1α and confirmed that the combination of this system with cisplatin exerted a synergistic antitumor effect. This study demonstrated that circHIF1α maintains ferroptosis resistance and a "high-iron metabolic" state in CSCs by preserving the antioxidant barrier, providing novel insights into the mechanism of circular RNAs and potential targets/strategies for overcoming chemotherapy resistance in ovarian cancer.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe