International Journal of Biological Sciences最新文献

{"title":"Bioactive Constituents of Ginseng in Cancer Therapy: Molecular Mechanisms, Translational Potential, and Advanced Delivery Strategies.","authors":"Jia-Hui Li, Yan-Fang Xian, De-Wen Liu, Hong-Yuan Li, Wei Li","doi":"10.7150/ijbs.136955","DOIUrl":"10.7150/ijbs.136955","url":null,"abstract":"<p><p>Cancer remains a major global health challenge, highlighting the urgent need to develop safer and more effective therapeutic drugs. Ginseng (<i>Panax ginseng</i> C.A. Mey.), as a medicinal plant widely used in traditional Chinese medicine, has attracted much attention for its extensive anticancer potential and a variety of biologically active ingredients (especially ginseng saponins and polysaccharides). This article reviews the latest research progress on the pharmacological activity and molecular mechanism of ginseng extract in cancer treatment, focusing on its inhibition of tumor growth, inducing cell apoptosis, inhibiting epithelial-mesenchymal transformation and metastasis, reshaping the tumor microenvironment, enhancing antitumor immunity, regulating metabolic reprogramming, and regulating epigenetics. In addition, this article also explores their potential to overcome multi-drug resistance and enhance the efficacy of traditional chemotherapy drugs. In recent years, a variety of drug delivery systems, including polymer nanoparticles, lipids, and micelles, have been developed to improve the bioavailability, stability, and tumor targeting of these compounds. This article also focuses on the current progress and challenges in clinical transformation, especially in the development and application of ginseng saponin preparations. In a word, this article provides a comprehensive review of ginseng-derived drugs from the perspective of pharmacology and translational medicine, and looks forward to the future direction of their reasonable development in cancer treatment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7800-7826"},"PeriodicalIF":11.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074572","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":"Histone demethylase KDM4A promotes endometrial cancer progression through an ERRγ-associated cell-cycle regulatory axis.","authors":"Junfeng Chen, Xiaoli Wen, Donghai Zhang, Mengyue Zhu, Hong Zhou, Yiran Li, Xiaoping Wan","doi":"10.7150/ijbs.133986","DOIUrl":"10.7150/ijbs.133986","url":null,"abstract":"<p><p>Endometrial cancer (EC) is driven by complex genetic and epigenetic alterations, but the specific chromatin-dependent mechanisms that sustain malignant proliferation remain incompletely understood. In this study, we found that lysine demethylase 4A (KDM4A) was upregulated in EC and promoted cell proliferation, migration, and invasion, accompanied by increased estrogen-related receptor gamma (ERRγ) expression. Mechanistically, KDM4A promoted ERRγ expression in association with reduced enrichment of the repressive H3K9me3 modification at the ESRRG promoter, suggesting that KDM4A may facilitate ESRRG transcription by attenuating H3K9me3-associated repression. Functionally, ERRγ acted as a downstream mediator associated with increased CDK1 transcription and elevated CDK1 and Cyclin B1 protein expression. These findings suggest that the KDM4A-ERRγ axis contributes to G2/M-phase regulation and EC cell proliferation. Importantly, treatment with the KDM4-family inhibitor QC6352 significantly suppressed EC cell growth <i>in vitro</i> and reduced xenograft tumor growth <i>in vivo</i>. These findings support a model in which KDM4A-associated reduction of H3K9me3 enrichment at the ESRRG promoter contributes to ERRγ upregulation and altered cell-cycle regulation in EC cells. Furthermore, these findings provide preliminary preclinical support for further investigation of KDM4-family inhibition as a potential therapeutic approach in EC.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7827-7844"},"PeriodicalIF":11.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074364","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":"Hippocampal NLRP3 Inflammasome Drives Anxiety- and Depressive-Like Behaviors Following Drug-Induced Liver Injury.","authors":"Hao Zhang, Jia-Lu Zhuang, Rui Ma, Sheng Wang, Jing Huang, Hui-Xia Yang, Ming-Ming Hu, Xiao-Li Wei, Hai-Yuan Shen, Hui Fang, Wen-Ning Wu, Hua Wang","doi":"10.7150/ijbs.128620","DOIUrl":"10.7150/ijbs.128620","url":null,"abstract":"<p><p>Drug-induced liver injury (DILI) is a considerable and potentially severe adverse reaction to medications. As drug abuse continues to rise, managing drug-induced liver toxicity has become a considerable challenge for clinicians. Depression is a chronic neurological disorder with a rising incidence globally in recent years, adding to the overall societal burden. Numerous clinical studies have suggested a link between DILI and mental illnesses, with inflammation potentially playing a mediating role. However, the exact mechanisms remain unclear. Here, we established a mouse model of DILI through acetaminophen (APAP) exposure and assessed the correlation between mental disorder and NLRP3 inflammasome. We found that DILI mice exhibited anxiety- and depressive-like behaviors, along with disrupted blood-brain barrier integrity and a significant increase in hippocampal NLRP3 inflammasome levels. <i>Nlrp3</i> knockout or hippocampal <i>Nlrp3</i> knockdown ameliorated DILI-induced anxiety- and depressive-like behaviors. Moreover, N-acetylcysteine, an agent against APAP-induced hepatotoxicity, inhibited NLRP3 inflammasome activation and alleviated anxiety- and depressive-like behaviors in DILI mice. These results indicate that the NLRP3 inflammasome might be a promising target for the treatment of patients with DILI who experience comorbid anxiety and depression.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7782-7799"},"PeriodicalIF":11.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074443","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 Iron Regulatory Protein 2 in Tumor-associated Macrophages Activates Antitumor Immunity in NSCLC via Modulating SphK1-PD-L1 Axis.","authors":"Jiawen Ding, Qinpei Cheng, Chen Cheng, Ying Mei, Liu Yang, Peilin Chen, Lei Zheng, Suhua Zhu, Kaikai Shen, Kuanyu Li, Tangfeng Lv","doi":"10.7150/ijbs.130591","DOIUrl":"10.7150/ijbs.130591","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. As a predominant immune cell population in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play a critical role in tumor progression and resistance to immune checkpoint inhibitors (ICIs). TAMs can promote either antitumor immunity or immunosuppression depending on their polarization status. Iron regulatory protein 2 (IRP2) is a key regulator of intracellular iron homeostasis and has been reported to be upregulated in several tumor types. However, the role of IRP2 in the TME remains unclear. This study revealed the previously unrecognized role of IRP2 in NSCLC progression and explored its potential as a TAM-directed therapeutic target linked to programmed death-ligand 1 (PD-L1) regulation. We found that IRP2 skewed TAMs toward an immunosuppressive state that promoted tumor cell proliferation and migration, and limited apoptosis. Furthermore, IRP2 may sustain PD-L1 expression in TAMs by limiting sphingosine kinase 1 (SphK1)-associated lysosomal degradation. In conclusion, our findings identify IRP2-dependent maintenance of the immunosuppressive TAM phenotype as a promising therapeutic target in NSCLC.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7928-7947"},"PeriodicalIF":11.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074468","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":"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":"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}