International Journal of Biological Sciences最新文献

{"title":"Genomic and Transcriptomic Landscapes of MEN1-Wild-Type Low-Grade Metastatic Pancreatic NETs Uncover Key Oncogenic Drivers and Targetable Pathways.","authors":"Md Hafiz Uddin, Zaid Mahdi, Irfana Muqbil, Brendon R Herring, Bart Rose, Husain Y Khan, Yiwei Li, Amro Aboukameel, Sahar F Bannoura, Hugo Jimenez, Allan M Johansen, Mohammed Najeeb Al-Hallak, Ibrahim Azar, Amr Mohamed, Tarik Hadid, Nitin Vaishampayan, Yang Shi, Yin Wan, Vy Ong, Gregory Dyson, Rafic Beydoun, Miguel Tobon, Eliza W Beal, Herbert Chen, Anthony F Shields, Philip A Philip, Jennifer Beebe-Dimmer, Ramzi M Mohammad, Boris C Pasche, Bassel F El-Rayes, Asfar S Azmi","doi":"10.7150/ijbs.134269","DOIUrl":"10.7150/ijbs.134269","url":null,"abstract":"<p><p>Sporadic pancreatic neuroendocrine tumors (pNETs) with wild-type MEN1 represent a major yet largely ignored subset whose biology and metastatic potential remain poorly understood. Because metastasis can occur despite low histologic grade and modest mutational burden, we hypothesized that metastatic competence in MEN1-wild-type pNETs reflects quantitative reinforcement of shared oncogenic pathways rather than distinct mutational processes. We profiled 75 primary WHO G1/G2 pNETs by whole-exome and RNA sequencing, including 25% with lymph node and/or liver metastasis, and integrated genomic and transcriptomic data to connect pathway lesions with expression state. Metastatic tumors showed a slight increase in mutation frequency but conserved base-substitution spectra relative to non-metastatic cases, and adverse clinicopathologic features were enriched in Grade 2 disease. Aggregating alterations to pathways revealed broad convergence on canonical networks, with transcriptomic analyses demonstrating cohort-wide enrichment of Calcium, WNT, and KRAS/PI3K-AKT programs in metastasis. Intersection of significantly mutated genes with differentially expressed genes identified a focused 29-gene overlap, including RYR1 and ZNF273, that marks these convergent axes and distinguishes metastatic from non-metastatic tumors. Gene set enrichment confirmed preferential activation of Calcium, WNT, and PI3K-AKT signaling in metastatic tumors, consistent with a network-intensity model of progression. Finally, upstream-regulator analysis (iPathwayGuide) and gene-centric perturbation mapping (Gene2Drug) nominated candidate targeted and repurposable agents predicted to reverse the metastatic expression phenotype and flagged drugs unlikely to provide benefit, yielding a prioritized, testable therapeutic shortlist which includes fasudil and spaglumic acid. Convergent, domain-specific mutational patterns in highly mutated genes such as ZNF273 and CLCA1 define a molecular signature that could stratify metastatic risk in low-grade pNETs. Functional validation identified ZNF273 and RYR1 as candidate effectors of metastatic fitness in MEN1-wild-type pNETs, as siRNA-mediated silencing reduced cell viability, clonogenicity, spheroid growth, and migration in BON1 and QGP1 models. Predicted compounds showed <i>in vitro</i> activity, with doxorubicin exhibiting the strongest cytotoxic effect, supporting a therapeutically tractable KRAB-ZNF/calcium signaling axis in metastatic pNETs. Collectively, our data reframe metastasis in MEN1-wild-type low-grade pNETs as a property of pathway state rather than mutation quantity and provide a translational blueprint for biomarker-guided therapy development focused on Calcium, WNT, and KRAS/PI3K hubs.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7908-7927"},"PeriodicalIF":11.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ezrin Functions as a Key Mechanosensitive Effector to Preserve Cell Structure and Promote Survival and Metastasis of Lung Cancer Cells during Circulation.","authors":"Xiaoying Zhang, Muya Zhou, Koukou Li, Mingheng Yuan, Haibo Tong, Kathy Qian Luo","doi":"10.7150/ijbs.127134","DOIUrl":"10.7150/ijbs.127134","url":null,"abstract":"<p><p>Metastasis remains the leading cause of cancer-related mortality, a process in which circulating tumor cells (CTCs) play a central but incompletely understood role. Although most CTCs are rapidly eliminated during circulation through detachment-induced anoikis and fluid shear stress (SS)-triggered apoptosis, a subset of CTCs can survive these hostile conditions; however, the underlying mechanisms remain poorly defined. To investigate this, we developed a microfluidic circulatory system that mimics physiological SS and performed transcriptomic profiling of A549 lung cancer cells under SS, attached, and static suspension conditions. Through this approach, we identified the ROS-CD44-Ezrin axis as a potential mechanosignaling module that may contribute to CTC survival under shear stress. In this cascade, SS-induced ROS and CD44 converge to activate Ezrin via phosphorylation at Thr567. Once activated, Ezrin appears to coordinate its two canonical functions-membrane-cytoskeleton reinforcement and pro-survival signaling via PI3K/AKT/Bcl-2 and NF-κB/p38/JNK pathways-within this specific mechanobiological context to preserve cell integrity and limit apoptosis. Our findings suggest that these well-established molecular functions are differentially engaged under shear stress, revealing a context-dependent survival mechanism that may offer opportunities for therapeutic exploration, pending further validation in more clinically relevant models.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7887-7907"},"PeriodicalIF":11.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Genomic Screening Identifies lncRNA CNPY2-AS1 as a Regulator of Redox Metabolism and Antiviral Immunity.","authors":"Carolina Khoury, Tahleel Ali-Nasser, Yuval Ben Eliahu, Haya Dahamshy Silawi, Liran Ben Yaakov, Simon Rousseau, Yvan Devaux, Nisrine Lahoud-Jeries, Assaf C Bester","doi":"10.7150/ijbs.132728","DOIUrl":"10.7150/ijbs.132728","url":null,"abstract":"<p><p>The human genome encodes thousands of long non-coding RNAs (lncRNAs) that regulate innate immunity and viral life cycles, yet their roles in viral entry remain understudied. Here, we conducted a genome-wide CRISPR interference screen to identify lncRNAs that regulate SARS-CoV-2 entry. We identified two lncRNAs that modulate angiotensin-converting enzyme 2 (ACE2) dependent viral entry through distinct mechanisms. Our findings suggest that the RP11-314A20.5 locus acts as a <i>cis</i>-regulatory element that modulates the expression of neighboring genes, including MED11 and CXCL16, linking this genomic region to host pathways associated with SARS-CoV-2 entry and COVID-19 severity. In contrast, CNPY2-AS1 functions in trans as a central regulator coupling cellular redox homeostasis to innate immune signaling. Mechanistically, CNPY2-AS1 associates with thioredoxin reductase 1 (TXNRD1), a key enzyme that limits reactive oxygen species. Loss of CNPY2-AS1 disrupts redox balance, triggering ligand-independent STAT1 activation and IRF7-mediated interferon and inflammatory responses. This dysregulated program has dual effects: induction of the interferon-stimulated gene PLSCR1 restricts viral entry by reducing cell-surface ACE2, while concurrent cytokine activation recapitulates features of pathological inflammation in severe COVID-19. Consistently, clinical datasets show reduced CNPY2-AS1 expression in patients with fatal disease. Together, these findings reveal distinct lncRNA-mediated mechanisms regulating SARS-CoV-2 entry and identify CNPY2-AS1 as a critical integrator of redox metabolism and innate antiviral immunity.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7760-7781"},"PeriodicalIF":11.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein Post-Translational Modifications in the Regulation of Ferroptosis: New Opportunities and Challenges for Cancer Immunotherapy.","authors":"Xin Xie, Lizhou Song, Zhaoyu Li, Jiahao Hu, Zhiheng Lin, Yadong Guo, Haoling Zhang, Wangzheqi Zhang, Zui Zou","doi":"10.7150/ijbs.135689","DOIUrl":"10.7150/ijbs.135689","url":null,"abstract":"<p><p>Ferroptosis is an emerging form of programmed cell death driven by the excessive accumulation of iron-dependent lipid peroxides, which plays a pivotal regulatory role in suppressing tumor initiation and progression. In recent years, protein post-translational modification (PTM), as a core molecular mechanism regulating protein function, stability, and subcellular localization, occupies a central position in the precise targeted regulation of ferroptosis. This review systematically summarizes and elucidates the core molecular regulatory mechanisms of ferroptosis, focusing on the dynamic regulatory pathways and effects of common protein PTM (including ubiquitination, phosphorylation, acetylation and lactylation) on key ferroptosis regulators. Meanwhile, it deeply analyzes the complex interactive regulatory network between ferroptosis and tumor immunity, and elaborates on the specific pathways by which ferroptosis remodels the tumor immune microenvironment through inducing immunogenic cell death (ICD) and releasing damage-associated molecular patterns (DAMPs). More importantly, this paper systematically discusses the potential application value of ferroptosis-related protein PTM in overcoming tumor immune escape, enhancing the antitumor activity of T cells and natural killer cells, and improving the clinical efficacy of immune checkpoint inhibitors (ICIs). Finally, it summarizes the core challenges existing in this research field and prospects the future development of novel PTM-based combination antitumor strategies targeting ferroptosis and personalized antitumor therapy. This review aims to provide new theoretical references and experimental evidence for the clinical prevention, treatment and intervention of malignant tumors.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7963-8007"},"PeriodicalIF":11.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human-Mouse Chimerism for Organogenesis Without Neural or Germline Contributions.","authors":"Sen Ye, Kailibinuer Kadier, Ye Yi, Guihui Qin, Borong Huang, Siyi Fu, Cantas Alev, Ren-He Xu","doi":"10.7150/ijbs.119609","DOIUrl":"10.7150/ijbs.119609","url":null,"abstract":"<p><p>Human pluripotent cells, including embryonic stem cells (ESCs), have been used for interspecies blastocyst complementation, with the potential to generate human organs in animals for clinical applications. However, ethical concerns exist as human cells may contribute to the germline and central nervous system (CNS) in chimeric animals. To prevent such concerns, here we generated <i>BLIMP1</i> and <i>PAX6</i> knockout human ESCs (hESCs) that are capable of contributing to all cell and tissue types, except the germline and CNS in human-mouse chimeras. To overcome the low chimerism efficiency of hESCs, we also engineered <i>BLIMP1^-/-</i> /<i>PAX6^-/-</i> hESCs with a doxycycline-inducible system to express the anti-apoptotic gene <i>BCL2</i> (<i>iBCL2</i>) and injected them into <i>Igf1r^-/-</i> mouse blastocysts, which remarkably enhanced the chimerism efficiency. To test organogenesis potential, mesenchymal stem cells were generated from <i>BLIMP1^-/-</i> /<i>PAX6^-/-</i> /<i>iBCL2⁺</i> hESCs injected into <i>Sox9^+/-</i> mouse blastocysts, which rescued <i>Sox9</i> haploinsufficiency skeletal defects and contributed to mesenchymal tissues of the chimeric fetuses and neonates. Thus, we provide a simple and effective approach to generating human-animal chimeras that are free of ethical concerns.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7948-7962"},"PeriodicalIF":11.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycolytic Reprogramming Mediated by the OTUD4-FXR1-HIF1A Axis Drives Gastric Cancer Progression.","authors":"Fulin Wang, Yu Shao, Xiaomei Zhuang, Xiumin Liu, Yu Hu, Chen Dai, Jia Chen, Yong Kuang, Gangqiang Wang, Zhenzhen Zhao, Nan Cai, Liang Gu, Guoying Zhou, Hongwu Chu, Huimin Zhao, Cuncan Deng, Changhua Zhang","doi":"10.7150/ijbs.138384","DOIUrl":"10.7150/ijbs.138384","url":null,"abstract":"<p><p>Ubiquitination and deubiquitination play critical roles in gastric cancer progression, yet systematic investigations of ubiquitin-regulating proteins in gastric cancer (GC) remain limited. To identify key regulators, we performed Ubiquitin-Focused CRISPR-Cas9 growth-based screening in GC cells and identified the deubiquitinase OTUD4 as a candidate gene promoting tumor growth. Functionally, OTUD4 was found to act as an oncogene by promoting the proliferation and metastasis of GC cell. Mechanistically, OTUD4 interacts with FXR1 through its N-terminal region (1-245 aa), and mutation of the catalytic cysteine residue (C45A) markedly impairs this interaction. OTUD4-mediated deubiquitination removes K48-linked polyubiquitin chains from FXR1, thereby protecting FXR1 from proteasomal degradation and increasing its stability. The resulting accumulation of FXR1 enhances HIF1A mRNA stability, leading to increased HIF1A expression. Consequently, HIF1A activates glycolytic programs and promotes the malignant progression of gastric cancer. Clinically, OTUD4 expression was significantly higher in tumor tissues, and higher OTUD4 levels were linked to decreased overall survival. Importantly, OTUD4 and FXR1 expression levels show a positive correlation in human GC samples. Collectively, these findings uncover an OTUD4-FXR1-HIF1A signaling axis that promotes glycolysis, which in turn functionally drives gastric cancer progression, and thereby provides a potential prognostic biomarker and therapeutic target.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7845-7861"},"PeriodicalIF":11.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated single-cell TCR analysis across tissue identifies GZMK⁺CD8⁺ T cells promoting fibrosis via TGF-β signalling in IPF.","authors":"Bingqing Yue, Shuliang Jing, Qiaxuan Li, Guoyu Xie, Juan Chen, Tao Yan, Ganggui Zhu, Bin Huang, Jin Zhao, Xiucheng Yang, Jian Huang, Pan Yin, Qifeng Yao, Huijing Yang, Fei Gao, Jun Yang, Man Huang, Jingyu Chen","doi":"10.7150/ijbs.134974","DOIUrl":"10.7150/ijbs.134974","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with progressive scarring and an unknown aetiology, but the cross-tissue immune network remains poorly understood. Here, we performed paired single-cell RNA sequencing and T cell receptor profiling of lung, mediastinal lymph node, and peripheral blood samples from patients with severe IPF. We identified a GZMK⁺CD8⁺ T cell subset enriched in fibrotic lung tissue with an inflammatory, low-cytotoxic phenotype, and a clonally related CD8_HSPA1A population enriched in lymph nodes, suggesting a cross-tissue clonal connection. Higher GZMK⁺CD8⁺ T cell signatures were associated with worse survival and impaired lung function. Functionally, GZMK overexpressing CD8⁺ T cells promoted fibroblast-to-myofibroblast differentiation and proliferation through TGF-β1/Activin A signalling, whereas GZMK knockdown attenuated these responses. Importantly, genetic ablation of GZMK markedly reduced collagen deposition and lung fibrosis in bleomycin-induced mice. Furthermore, inhibition of TGFβR1/ALK4 using the inhibitor TEW-7197 effectively suppressed fibroblast activation in vitro and significantly attenuated pulmonary fibrosis in bleomycin-induced mice. Together, these findings suggest a potential profibrotic immune-stromal circuit in severe IPF in which GZMK⁺CD8⁺ T cells promote fibroblast activation through TGF-β1/Activin A signalling, highlighting this pathway as a potential therapeutic target.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7862-7886"},"PeriodicalIF":11.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting tubular NAT10 ameliorates the renal Tubulointerstitial Fibrosis in Obstructive and Folic Acid-Induced Nephropathy.","authors":"Qin Kang, Lin Yin, Chenkai Wu, Wende Yan, Sai Peng, Jinfang Lu, Dongshan Zhang","doi":"10.7150/ijbs.135844","DOIUrl":"10.7150/ijbs.135844","url":null,"abstract":"<p><p>Renal tubulointerstitial fibrosis (TIF) represents a common pathological hallmark during the progression of chronic kidney disease (CKD). NAT10, an RNA acetyltransferase, catalyzes N4-acetylcytidine modification of mRNA and has been associated with multiple pathological events, including bladder cancer progression, tumor metastasis, and cardiac remodeling. Nevertheless, NAT10's precise function and underlying molecular mechanisms in TIF remain inadequately elucidated. In this investigation, transforming growth factor-β1 (TGF-β1) was found to promote NAT10 expression in BUMPT cells via p53 upregulation. Functionally, NAT10 was demonstrated to regulate FN, Collagen I, and Collagen III expression triggered by TGF-β1 stimulation. Mechanistically, NAT10 enhanced Spred2 expression by promoting acetylation-dependent mRNA stability, which subsequently activated the JNK and ERK/TGF-β signaling pathways. Furthermore, a renal tubular epithelial cell-specific NAT10 knockout mouse model was established, and NAT10 deficiency's influence on TIF progression was examined using unilateral ureteral obstruction (UUO)- and folic acid (FA)-induced renal fibrosis models. The findings indicated that tubular epithelial-specific NAT10 deletion markedly alleviated UUO- and FA-induced renal TIF via inhibiting Spred2/JNK and ERK/TGF-β signaling. Finally, 5-Fluorouridine, a potent ribozyme self-cleavage inhibitor, was observed to attenuate UUO- and FA-induced renal TIF by targeting NAT10. Collectively, a previously unrecognized p53/NAT10/Spred2/JNK and ERK/TGF-β regulatory axis driving renal TIF is identified, and 5-Fluorouridine represents a viable therapeutic intervention for renal TIF.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7667-7685"},"PeriodicalIF":11.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tubular NAT10 Promotes the Secretion of TGF-β and Lactate to Drive Fibroblast Activation in Diabetic Kidney Disease.","authors":"Jinfang Lu, Yuqing Feng, Xujun Peng, Zijin He, Zhou Li, Ao Jia, Yaohui Bao, Lingui Xie, Renchun Wang, Wenbo Zhang, Qin Kang, Yanyan Zhou, Cheng Wang, Hongquan Peng, Huiling Li, Dongshan Zhang","doi":"10.7150/ijbs.140281","DOIUrl":"10.7150/ijbs.140281","url":null,"abstract":"<p><p>In advanced diabetic kidney disease (DKD), tubulointerstitial fibrosis (TIF) is a key histopathological lesion accompanying progressive renal functional decline. However, the tubular mechanisms that drive tubulointerstitial fibrogenesis remain incompletely understood. N-acetyltransferase 10 (NAT10) mediates mRNA N4-acetylcytidine (ac4C) modification, but its role and therapeutic potential in DKD are unknown. We investigated NAT10 regulation and function using cultured tubular cells, diabetic mouse models, patient kidney specimens, and tubule-specific Nat10 knockout mice, together with pharmacological treatment using guanosine diphosphate disodium salt. High glucose or diabetes increased tubular NAT10 abundance in cultured cells, mouse kidneys, and human DKD tissues through activation of NF-κB signaling. Mechanistically, NAT10 in tubular cells stabilized <i>Brd4</i> and <i>Pfkm</i> mRNAs through ac4C modification, activating the STAT3/TGF-β and lactate/H3K18 lactylation pathways. These pathways synergistically promoted fibroblast activation through NOTCH/SMAD3 signaling and formed a positive feedback loop with NF-κB. Tubule-specific <i>Nat10</i> deletion reduced <i>Brd4</i> and <i>Pfkm</i> expression, suppressed the associated signaling cascades, and mitigated kidney fibrosis in the DKD model. Consistently, guanosine diphosphate disodium salt alleviated renal injury and fibrosis in <i>db/db</i> mice. Thus, NAT10 drives tubular fibrosis through ac4C-dependent profibrotic signaling, supporting NAT10 inhibition as a potential therapeutic strategy for DKD.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7737-7759"},"PeriodicalIF":11.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAF-derived BHB modulates FXR1-Kbhb and NK-cell lipid metabolism in osteosarcoma.","authors":"Yihan Yu, Wei Wu, Anzhen Ju, Lei Zhao, Guohui Liang, Yun Liu, Zengwu Shao, Feifei Pu, Binlong Zhong, Fengxia Chen, Jianxiang Liu, Zhicai Zhang","doi":"10.7150/ijbs.128764","DOIUrl":"10.7150/ijbs.128764","url":null,"abstract":"<p><p>Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents and is characterized by high aggressiveness and poor prognosis. Although surgery and chemotherapy have improved overall survival, outcomes for relapsed or metastatic disease remain extremely poor, thus underscoring the urgent need for novel therapeutic strategies. Natural killer (NK) cells are key cytotoxic effectors in tumor immunity, but their function is profoundly suppressed within the OS tumor microenvironment. Furthermore, the role of cancer-associated fibroblasts (CAFs) in mediating NK-cell dysfunction through metabolic regulation remains insufficiently understood. We established coculture systems of NK cells, OS cells, and CAFs and assessed NK-cell activation and cytotoxicity by using functional assays, flow cytometry, and immunofluorescence. Metabolic profiling was performed with extracellular acidification rate, oxygen consumption rate, reactive oxygen species detection, MitoTracker staining, and electron microscopy. Integrated proteomics and mechanistic studies were used to identify CAF-derived metabolites and their effects on NK-cell metabolism. CAFs markedly impaired NK-cell recognition and cytotoxicity toward OS cells, accompanied by metabolic reprogramming characterized by enhanced glycolysis, increased reactive oxygen species production, and reduced mitochondrial activity. Multiomics and functional analyses identified β-hydroxybutyrate (BHB) as a key CAF-derived metabolite that contributed to reduced NK-cell FAO and effector function. BHB treatment increased FXR1 Kbhb and reduced FAO, cytokine secretion, and tumor-cell killing, whereas FXR1 K56 mutation attenuated these functional changes. <i>In vivo</i>, CAF-CM treatment was accompanied by elevated circulating BHB, reduced NK-cell activation, and accelerated tumor growth. Targeting the CAF-BHB- FXR1 axis may represent a promising therapeutic strategy to restore NK cell-mediated antitumor immunity and improve treatment outcomes.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7714-7736"},"PeriodicalIF":11.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}