International Journal of Biological Sciences最新文献

{"title":"Margin-enriched CD4⁺ central-memory T cells affect macrophages via ANXA1-FPR1 signaling axis to promote tumor progression in intrahepatic cholangiocarcinoma.","authors":"Zhifeng Jiang, Ao Huang, Runze Miao, Shiyu Zhang, Feiyu Chen, Yang Xu, Jiayan Yan, Lixing Li, Senquan Zhang, Rongkui Luo, Wen Huang, Haixiang Sun, Xinrong Yang, Jian Zhou","doi":"10.7150/ijbs.136469","DOIUrl":"10.7150/ijbs.136469","url":null,"abstract":"<p><p>Intrahepatic cholangiocarcinoma (iCCA) is the second most prevalent liver cancer with a high mortality and recurrence rate, and remains a poorly understood disease. The tumor margin, as the transition zone between normal tissue and tumor, was not appreciated before. We performed mass cytometry (cytometry by time of flight, CyTOF) on 30 samples from iCCA tumor, paratumor and margin tissue. We found that the number of CD4⁺ central memory T cells (CD4⁺ T_cm) increased in the margin zone. Single cell RNA-seq (scRNA-seq) further discovered that CD4⁺ T_cm cells enriched in the margin zone of iCCA exhibited upregulated Annexin A1 (ANXA1) expression. Fibroblasts recruited CD4⁺ ANXA1⁺ T_cm cells via Chemokine (C-C motif) ligand 19 (CCL19)-Chemokine (C-C motif) receptor 7 (CCR7) signaling pathway. The molecular characteristics of CD4⁺ ANXA1⁺ T_cm in iCCA were characterized, and the interactions between these T cells and other cells were determined. Patients with enriched CD4⁺ ANXA1⁺ T_cm cells in the tumor margin exhibited a worse prognosis. Specifically, CD4⁺ ANXA1⁺ T_cm cells could recruit macrophages to the tumor margin and regulate the macrophage polarization via the ANXA1-Formyl Peptide Receptor 1 (FPR1) signaling axis. CD4⁺ ANXA1⁺ T_cm cell-activated macrophages could enhance the invasion and proliferation of tumor cells by exerting different cytokines. In conclusion, our study systematically characterized the features and distribution of CD4⁺ ANXA1⁺ T_cm cells in the margin zone of iCCA. We investigated the potential mechanisms by which CD4⁺ ANXA1⁺ T_cm cells affected tumor progression, and provided novel understanding of the function of these CD4⁺ T_cm cells in iCCA.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7225-7239"},"PeriodicalIF":11.7,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887118","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":"AMOTL2 inhibits lymph node metastasis in gastric cancer by suppressing TGF-β/Smad signaling and is destabilized by the E3 ubiquitin ligase SMURF1.","authors":"Huizhen Wang, Bo Yang, Changqing Lin, Yigao Wang, Yida Lu, Jing Li, Jianhui Li, Kexun Yu, Mingliang Wang, Pengpeng Liu, Yuexiang Wang, Yongxiang Li","doi":"10.7150/ijbs.135795","DOIUrl":"10.7150/ijbs.135795","url":null,"abstract":"<p><p>Angiomotin-like protein 2 (AMOTL2) regulates cell polarity and cytoskeletal regulation, but its role in gastric cancer (GC) remains undefined. Here, we show that AMOTL2 is frequently downregulated in GC tissues and cell lines, and its low expression is associated with deeper tumor invasion, lymph node metastasis, and shorter overall survival. Gain- and loss-of-function assays demonstrated that AMOTL2 suppresses GC cell proliferation, migration, and invasion. AMOTL2 overexpression also impaired endothelial and lymphatic-endothelial tube formation and reduced the expression of angiogenic and lymphangiogenic factors. In the subcutaneous, orthotopic, and popliteal lymph node metastasis models, AMOTL2 inhibited tumor growth and lymphatic dissemination. Mechanistically, AMOTL2 suppressed TGF-β/Smad signaling, as evidenced by reduced BMP2 and TGF-β1 expression, decreased Smad1/5/9 and Smad2/3 phosphorylation, and impaired Smads nuclear accumulation. Notably, pharmacological Smad1/5/9 activation by SB4 partially reversed the suppressive phenotypes of AMOTL2 <i>in vitro</i> and <i>in vivo</i>. Co-immunoprecipitation, GST pull-down, and ubiquitination assays identified SMURF1 as an AMOTL2-interacting E3 ubiquitin ligase that binds through its WW domains and promotes AMOTL2 ubiquitination and proteasomal degradation. AMOTL2 restoration counteracted SMURF1-driven malignant phenotypes. Collectively, these findings define AMOTL2 as a potential suppressor of GC progression that is destabilized by SMURF1, suggesting that the SMURF1-AMOTL2-Smad signaling axis may contribute to GC progression and lymphatic dissemination, representing a candidate therapeutic target that warrants further validation.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7191-7208"},"PeriodicalIF":11.7,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886963","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":"Post-Translational Modifications in Cancer-Associated CD8⁺ T-Cell Exhaustion: Mechanisms and Therapeutic Opportunities.","authors":"Yongqi Lv, Qihang Shang, Yang Yu, Yahui Fu, Lijuan Liu, Changgang Sun","doi":"10.7150/ijbs.138638","DOIUrl":"10.7150/ijbs.138638","url":null,"abstract":"<p><p>CD8⁺ T-cell exhaustion is a distinct differentiation state driven by persistent antigen stimulation, and its establishment and maintenance are major barriers to effective cancer immunotherapy. Although the transcriptional and epigenetic landscapes of exhausted CD8⁺ T cells have been extensively characterized, it remains unclear how sustained external stimulation is integrated at the level of protein function to produce stable dysfunction and altered cell fate. Post-translational modifications constitute a key regulatory layer of protein function. They form a dynamic network that links persistent antigenic stimulation and tumor microenvironmental stress to cell fate, and therefore provide a critical entry point for understanding how exhaustion is initiated and maintained. In this review, we focus on how post-translational modifications convert persistent antigen stimulation and tumor microenvironmental stress into protein-level dysregulation and ultimately lock CD8⁺ T cells into an exhausted fate. We summarize how multiple classes of post-translational modifications drive exhaustion through effects on signal transduction, protein homeostasis, metabolic stress responses, and epigenetic reprogramming. We then discuss potential intervention strategies centered on critical regulatory nodes that may preserve the plasticity of precursor exhausted CD8⁺ T cells, restrain stabilization of the terminally exhausted state in CD8⁺ T cells, and optimize rational combination therapies. Finally, we outline the translational challenges and future directions of targeting post-translational modifications, and emphasize that identifying actionable modification nodes will be important for patient stratification and combination design in cancer immunotherapy.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7053-7081"},"PeriodicalIF":11.7,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887132","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":"Pharmacological Blockade of NMUR2 Suppresses Glioma Growth by Inhibiting STAT5-Mediated Transcription of Cell Cycle-associated Genes.","authors":"Yuna Roh, Taesang Son, Tae-Hee Han, Sarang Kim, Eunsun Jung, Jin-Seong Hwang, Joo-Young Im, Mi-Jung Kang, Mun Jeong Cho, Jung Hwa Lim, Cho-Rok Jung, Moo-Seung Lee, Hyun-Soo Cho, Dae-Soo Kim, Mi-Young Son, Seon-Young Kim, Seon-Kyu Kim, Hyun Seung Ban, Jang-Seong Kim, Tae-Su Han","doi":"10.7150/ijbs.135596","DOIUrl":"10.7150/ijbs.135596","url":null,"abstract":"<p><p>Glioma is a highly aggressive brain tumor with poor prognosis and limited therapeutic options. Although temozolomide (TMZ) remains the standard chemotherapeutic agent for glioma, frequent recurrence and the development of therapeutic resistance continue to limit clinical benefit, highlighting the need for new molecular targets and treatment strategies. Here, we identify neuromedin U receptor 2 (NMUR2) as a driver of glioma progression and a potential therapeutic target. NMUR2 expression was markedly elevated in glioma tissues and positively associated with tumor grade. Functional analyses showed that NMUR2 promoted glioma cell proliferation and migration, whereas NMUR2 silencing attenuated these malignant phenotypes. Mechanistically, NMUR2 activated Gαq-dependent Ca²⁺ signaling, leading to STAT5 phosphorylation and subsequent transcriptional upregulation of the cell cycle-associated genes PIM1 and FOXM1. Drug-repurposing screening of 6,331 compounds identified NNC 05-2090 as a candidate NMUR2 antagonist. NNC 05-2090 blocked NMUR2-mediated Gαq/Ca²⁺/STAT5 signaling, which was associated with reduced PIM1 and FOXM1 expression, cell cycle arrest, and suppression of glioma growth <i>in vitro</i> and <i>in vivo</i>. In addition, combination treatment with TMZ produced synergistic anti-tumor effects in glioma models. Collectively, our findings define a previously unrecognized NMUR2/Gαq/STAT5/PIM1-FOXM1 signaling axis in glioma and support pharmacological inhibition of NMUR2 as a potential therapeutic strategy.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7151-7172"},"PeriodicalIF":11.7,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887152","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 Folate Receptors for the Detection and Selective Treatment of Cancer: Advanced Precision Oncology in Practice.","authors":"Michal Stark, Yehuda G Assaraf","doi":"10.7150/ijbs.139733","DOIUrl":"10.7150/ijbs.139733","url":null,"abstract":"<p><p>The modern era of precision oncology strives to identify novel and selective druggable targets that, on the one hand, achieve efficacious anti-tumor activity, and on the other hand inflict minimal adverse effects to healthy tissues. The realization that both the tumor microenvironment and the tumor immune microenvironment (TIME) modulate tumor progression and response to chemotherapeutics, has pushed tumor-associated immune cells to the forefront as <i>bona fide</i> druggable targets. Based on their unique overexpression pattern on the cell surface of specific human malignancies and suppressor immune cells, folate receptors FRα and FRβ constitute optimal facilitators of noninvasive cancer detection and localization, as well as efficacious selective delivery of potent therapeutic payloads. Along this vein, this review highlights recent advanced strategies utilizing FR-targeting for precise tumor and metastatic lesion localization for guided surgical precision resection, potent anti-cancer efficacy and reprogramming of the suppressive TIME. Notably, these activities were accomplished with minimal side effects to healthy tissues. AZD5335, a recent clinically tested FRα-targeted antibody-drug conjugate carrying a topoisomerase I inhibitor payload, exceeded its predecessors by demonstrating remarkable efficacy against low FRα-expressing tumors as well. Thus, FRs emerge as selective and promising targets for advanced precision oncology of various malignancies including those displaying chemoresistance.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7018-7052"},"PeriodicalIF":11.7,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887166","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":"Calcitriol Modulates Age-dependent Drug Response in Paired Patient-derived Normal and Tumor Colorectal Organoids.","authors":"Asunción Fernández-Barral, Antonio Barbáchano, Silvia Rodríguez-Marrero, Luis Del Peso, Alfonso Herreros-Cabello, Estrella Arroyo-Gascón, Nuria Rodríguez-Salas, Isabel Prieto, Aurora Burgos, Miguel León-Arellano, Damián García-Olmo, Tomás Olleros, José Manuel González-Sancho, María Jesús Larriba, Alberto Muñoz","doi":"10.7150/ijbs.131639","DOIUrl":"10.7150/ijbs.131639","url":null,"abstract":"<p><p>The incidence of early-onset colorectal cancer (EO-CRC, <50 years) is rising worldwide, highlighting the need to better understand the underlying causes of this age-related divergence. We used paired patient-derived normal and tumor colorectal organoids to investigate the therapeutic window of chemotherapeutic agents and its modulation by calcitriol (the most active vitamin D metabolite). Dose-response analyses revealed marked interpatient variability, with SN38 being more potent than 5-fluorouracil (5-FU) and oxaliplatin. Normal organoids were more resistant than paired tumor counterparts to 5-FU and oxaliplatin in both EO-CRC and late-onset CRC (LO-CRC, >50 years), indicating selective tumor cytotoxicity. In contrast, the therapeutic window for SN38 was preserved in LO-CRC but not in EO-CRC organoids, revealing age-dependent differences in drug sensitivity. Moreover, calcitriol reduced the cytotoxicity of 5-FU and SN38 in normal organoids regardless of patient age, while in tumor organoids this protective effect was restricted to EO-CRC. As a consequence, calcitriol treatment selectively expanded the therapeutic window for 5-FU and SN38 in LO-CRC organoids. Mechanistically, these effects correlated with calcitriol-induced antiproliferative action and transcriptional regulation of drug metabolism-related pathways. Overall, our findings identify age-dependent differences in chemotherapy response and support the importance of maintaining adequate vitamin D status to reduce chemotherapy-associated toxicity.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7003-7017"},"PeriodicalIF":11.7,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887082","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":"Elimination of Senescent Macrophages by Purinergic Receptor P2RX7 Antagonist to Safeguard Against Kidney Injury and Aging.","authors":"Lei Tang, Letian Yang, Ruijia Zhang, Jian Li, Fan Guo, Haoyu Ye, Ping Zhou, Fei Liu, Liang Ma, Ping Fu","doi":"10.7150/ijbs.138299","DOIUrl":"10.7150/ijbs.138299","url":null,"abstract":"<p><p>Macrophage senescence is a pathological feature in aging or diseased kidneys. However, the role of senescent macrophages in kidney injury and aging has not been fully elucidated yet. We integrated the analysis of single-cell RNA sequencing datasets and the adoptively transfusion of pretreated bone marrow-derived macrophages to investigate the role of renal macrophage senescence in kidney injury. Here, we portrayed the senescence trajectory along multiple time points in infiltrating macrophages, and observed the persistent increase of macrophage-expressed purinergic receptor P2RX7 along the senescence trajectory in injured kidneys of septic mice. Importantly, our discovered small-molecule P2RX7 antagonist strikingly improved kidney function and pathological damage, as well as mitigated macrophage senescence in septic and aging mice. Mechanistically, P2RX7 antagonist could promote the wound healing, migration and proliferation capacity of senescent reparative macrophages, thus exerting anti-inflammatory effects and repairing kidney tissues. Together, our findings illustrate the crucial participation of senescent macrophages in septic kidney injury, and offer novel therapeutic strategy via intervening P2RX7 against immunosenescence-associated kidney injury and aging.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7082-7099"},"PeriodicalIF":11.7,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887085","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":"Neutrophil extracellular traps promote neuronal ferroptosis through STING-mediated AMPK dysregulation after traumatic brain injury.","authors":"Guihong Shi, Jianye Xu, Yue Tian, Yiyao Cao, Shaochen Yu, Qifeng Li, Luyuan Zhang, Kaiyuan Huang, Rui Tan, Xiujue Zheng, Renya Zhan","doi":"10.7150/ijbs.130882","DOIUrl":"10.7150/ijbs.130882","url":null,"abstract":"<p><p>Neuronal ferroptosis exacerbates neurological dysfunction after traumatic brain injury (TBI), yet the upstream signals driving this process remain poorly defined. Here, we identify neutrophil extracellular traps (NETs) as critical mediators of post-TBI ferroptotic injury. In patients, NET accumulation closely accompanied markers of neuronal ferroptosis and correlated with neurological severity. In a mouse TBI model, genetic ablation of peptidylarginine deiminase 4 (PAD4) or enzymatic degradation of NET-derived DNA markedly attenuated neuronal lipid peroxidation, suppressed ferroptosis-associated neuronal injury, and improved functional outcomes. Mechanistically, NET-derived DNA activated neuronal stimulator of interferon genes (STING) signaling, leading to suppression of intrinsic antioxidant defenses and amplification of lipid peroxidation. Pharmacological inhibition of STING or activation of AMP-activated protein kinase (AMPK) signaling effectively counteracted NET-induced ferroptotic stress and preserved neuronal viability. Collectively, these findings establish NET-derived DNA as a key upstream regulator of neuronal ferroptosis after TBI and highlight neutrophil-driven oxidative stress as a promising therapeutic target for secondary brain injury.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7100-7126"},"PeriodicalIF":11.7,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887122","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":"Deficiency of GLUT1 in macrophages reprograms tumor-associated macrophages to normalize tumor vasculature and retards the progression of tumors.","authors":"Yuan Fang, Wei Zou, Ling Ning, Tianle Li, Ying Huang, Xiaoxiong Song, Mengyuan Gao, Ruiqin Jia, Mingxi Zhu, Wenshi Qiu, Kexin Liu, Aiyun Wang, Jia Li, Yin Lu, Yang Zhao","doi":"10.7150/ijbs.131425","DOIUrl":"10.7150/ijbs.131425","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs), a major glucose-consuming population within the tumor microenvironment (TME), utilize glycolysis to support tumor progression. Therefore, concentrating on the glycolysis of intratumoral TAMs appears to be a promising research direction for tumor therapy. In this study, we demonstrated that the key glycolytic component named glucose transporter protein 1 (GLUT1, also known as SLC2A1) is extensively expressed in TAMs and is frequently associated with tumor progression. To dissect the functions of GLUT1 in macrophages on influencing the TME, macrophage-specific <i>Glut1</i> knockout mice were generated and tumor-bearing mouse models were established. It was found that macrophage-specific deletion of Glut1 retarded the development of tumors and reshaped the tumor immune microenvironment (TIME). Loss of <i>Glut1</i> in macrophages limited the secretion of multiple inflammatory mediators, including IL-6, IL-10, VEGF, and CXCL2, by virtue of the GSK3β/β-catenin/CD36 signaling axis, thereby normalizing the tumor blood vessels. To pharmacologically manipulate the expression of Glut1 in macrophages, M2-PLGA@WZB117 (poly lactic-co-glycolic acid, PLGA) was constructed accordingly. Interestingly, M2-PLGA@WZB117 resulted in significant inhibition in tumor progression, accompanied by tumor vascular normalization and a concurrent increase in the infiltration of CD8⁺ T cells. Therefore, our study provides new insights into reprogramming TAMs to exert impacts on tumor endothelium and thus regulating the TME, thereby hindering the development of tumors.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7127-7150"},"PeriodicalIF":11.7,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887172","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":"DHA Targets RAB1B to Mediate the Driving Force Transmission of Copper Ion Vesicular Endocytosis Under Copper Overload for Promoting Cuproptosis and Ferroptosis in Hepatic Stellate Cells.","authors":"Xinran Qiu, Haoyuan Tian, Shujiang Sun, Ningyu Qiu, Biao Xu, Junrui Wang, Yuanyuan Gao, Zhengyang Bao, Xiang Han, Jie Zeng, Yuxin Lin, Feng Zhang, Shizhong Zheng, Jiangjuan Shao","doi":"10.7150/ijbs.134520","DOIUrl":"10.7150/ijbs.134520","url":null,"abstract":"<p><p>Liver fibrosis represents a central pathological process in chronic liver diseases and poses a severe threat to human health. Cuproptosis, a copper ion-dependent form of regulated cell death, offers a potential therapeutic strategy for liver fibrosis. This study demonstrated that dihydroartemisinin (DHA) transiently upregulates SLC31A1, thereby promoting copper influx. Under copper overload, SLC31A1 undergoes ubiquitin-mediated degradation, while DHA targets RAB1B to activate RAB10-dependent vesicular endocytosis as a compensatory mechanism for sustained copper accumulation. This endocytic process alters cellular biomechanical properties and strengthens RAB1B-VDAC1 interaction to promote mitochondrial copper uptake. Following cuproptosis, iron-sulfur cluster proteins undergo degradation, leading to massive iron release and subsequent ferroptosis, establishing a cascading dual cell death mechanism. Mechanistically, RAB1B regulates KAT2A-mediated succinylation of USP11, thereby inhibiting USP11's deubiquitinating activity and accelerating SLC31A1 degradation. For <i>in vivo</i> applications, we engineered biomimetic nanoliposomes coated with HSC membranes and surface-functionalized with CD47, FNIII10, and ApoE. This system integrates immune evasion, hepatic accumulation, and HSC-specific recognition capabilities, demonstrating remarkable targeting efficacy and mechanistic consistency in primary HSCs and rodent models. These findings reveal that DHA enhances copper-laden vesicular endocytosis by targeting RAB1B, thereby triggering cuproptosis and ferroptosis, and provide novel molecular targeting strategies for liver fibrosis therapy.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"6914-6944"},"PeriodicalIF":11.7,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887111","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}