International Journal of Biological Sciences最新文献

{"title":"Hyperglycemia in Diabetes Drives Hepatic Fibrosis Through the Non-Enzymatic Function of HK2 and AGEs-mediated Matrix Stiffening.","authors":"Chuxin Huang, Jiali Qian, Li Zhang, Ying Liu, Qiwen Zhou, Jiajun Li, Yingying Zhao, Hongmei Yu, Yawen Zhang, Jinya Huang, Miao Li, Ziyu Ren, Zihao Xu, Rui Liu, Xuanchun Wang, Jie Chen, Jiefeng Cui, Yehong Yang","doi":"10.7150/ijbs.130351","DOIUrl":"10.7150/ijbs.130351","url":null,"abstract":"<p><p>Diabetes is implicated in accelerating the progression of hepatic fibrosis, and empagliflozin (an SGLT2 inhibitor) has potential therapeutic effects on diabetic hepatic fibrosis. However, their underlying mechanisms are still largely uncharacterized. In this study, we found that diabetes obviously promoted hepatic fibrosis progression, and empagliflozin intervention effectively impeded this pathological process independent of its hypoglycemic effects. Mechanistically, high glucose stimulation significantly increased HSC activation and its metabolic enzyme HK2 dissociation from mitochondria. The dissociated HK2 interacted with STAT3 to increase its nuclear entry for upregulating HSC activation-associated gene expression. Meanwhile, high glucose stimulation also suppressed KLF4 expression to attenuate its inhibitory effect on STAT3 transcription activation in HSCs. Additionally, high glucose-induced AGEs accumulation resulted in matrix stiffening, which also increased HSC activation. Empagliflozin alleviated hepatic fibrosis progression through decreasing AGEs accumulation and suppressing STAT3 and FOXO1 phosphorylation in HSCs. From the new perspectives of the non-metabolic functions of metabolic enzymes and matrix biomechanics, this study sheds light on a new synergistic regulatory pathway through which diabetes promotes hepatic fibrosis and highlights empagliflozin as a potential therapeutic agent for diabetic hepatic fibrosis.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7533-7556"},"PeriodicalIF":11.7,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074487","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":"Orthotopic Porcine Liver and Kidney Xenotransplantation as a Step Toward Multi-Organ Replacement.","authors":"Hwijin Kim, Jongwon Byun, Sun-Uk Kim, Taeho Kwon, Kyungjun Uh","doi":"10.7150/ijbs.139541","DOIUrl":"10.7150/ijbs.139541","url":null,"abstract":"","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7487-7490"},"PeriodicalIF":11.7,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891551","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":"Bazedoxifene Targets gp130 Signaling to Suppress Fibroblast Activation in Pathological Cutaneous Fibrosis: Insights from Spatial Transcriptomics and scRNA-seq Data.","authors":"Zixin Wang, Hanrui Zhang, Liying Tu, Jingjing He, Rong Wang, Yinghong Su, Siwei Tang, Qingfeng Li, Wenzheng Xia, Yashan Gao, Yixuan Zhao, Xin Huang, Tao Zan","doi":"10.7150/ijbs.137778","DOIUrl":"10.7150/ijbs.137778","url":null,"abstract":"<p><p>Pathological cutaneous fibrosis, exemplified by hypertrophic scarring and keloid formation, imposes substantial disease burden through persistent pruritus, pain and contracture-induced functional impairment. While the antifibrotic role of gp130 signaling inhibition has been established in visceral organ fibrosis, its therapeutic efficacy in pathological cutaneous fibrosis remains unexplored. Herein, we investigated the effectiveness of gp130 inhibition on cutaneous fibrosis by leveraging the application of Bazedoxifene, a clinically approved selective estrogen receptor modulator recently identified as a gp130 signaling inhibitor. We demonstrate that gp130 signaling is aberrantly activated in human keloid tissues and fibroblasts. <i>In vitro,</i> Bazedoxifene suppressed the fibroblast activation of disease-derived fibroblasts, featured by attenuated cell migration, myofibroblast differentiation and ECM production. <i>In vivo</i>, Bazedoxifene ameliorated dermal fibrosis and ECM deposition in both bleomycin-induced cutaneous fibrosis and keloid xenograft models. Notably, spatial transcriptomic analysis revealed reduced myofibroblast differentiation within fibrotic regions, providing tissue-level evidence for inhibition of fibroblast activation. Transcriptomic analysis revealed suppression of multiple fibrosis-associated signaling pathways following Bazedoxifene treatment, including the PI3K-AKT-mTOR, JAK-STAT, and MAPK pathways, with the PI3K-AKT-mTOR pathway showing the most prominent inhibition. Collectively, these findings establish Bazedoxifene repurposing as a promising therapeutic strategy for cutaneous fibrosis.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7491-7511"},"PeriodicalIF":11.7,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074563","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":"Dysregulation of the Upb1-3-ureidopropionate Pathway Impairs Fatty Acid Metabolism and Exacerbates Acute Kidney Injury.","authors":"Yu Zhang, Jia He, Runxin Zeng, Mingzhu Jiang, Shuang Xu, Yuxian Guo, Yue Zhang, Zhanjun Jia, Ran You, Mengqiu Wu, Aihua Zhang, Mi Bai","doi":"10.7150/ijbs.135329","DOIUrl":"10.7150/ijbs.135329","url":null,"abstract":"<p><p>Acute kidney injury (AKI) is a prevalent clinical syndrome associated with high mortality and lacking effective therapies, largely due to incomplete understanding of its pathogenic mechanisms. Proximal tubular epithelial cells (PTECs), with their high metabolic demand, represent the primary targets of injury in AKI. We identified β-ureidopropionase 1 (Upb1), a key enzyme in pyrimidine catabolism, as being specifically enriched in PTECs but markedly downregulated upon AKI. Genetic silencing of Upb1 exacerbated IR-induced AKI. Targeted metabolomics revealed that loss of renal Upb1 drives accumulation of 3-ureidopropionate (3-UPA), a pyrimidine catabolic intermediate. Integrated multi-omics analyses and functional validation demonstrated that 3-UPA impairs fatty acid oxidation through DNMT1-mediated DNA methylation, leading to mitochondrial structural and functional defects. Transcription factor analysis further revealed that myeloid ecotropic viral integration site 1 (Meis1) transcriptionally represses Upb1. Tubule-specific Meis1 overexpression aggravated folic acid (FA)- and ischemia/reperfusion injury (IR)-induced AKI, whereas pharmacological inhibition of Meis1 alleviated tubular damage. Notably, Meis1 overexpression induced marked 3-UPA accumulation, reinforcing its role as an upstream regulator of this metabolic axis. Collectively, these results demonstrate that Meis1/Upb1/3-UPA axis exerted a detrimental role in AKI, and targeting this axis (inhibiting Meis1 or activating Upb1) has therapeutic potential for AKI.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7644-7666"},"PeriodicalIF":11.7,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074088","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":"Cross-tissue single-cell atlas reveals Id2 promotes sepsis-induced tissue damage by mediating macrophage metabolic reprogramming via Pkm2.","authors":"Xiaodan Wang, Yiyan Liu, Yuanqun Zhou, Liyong Zou, Xiaowei Zhou, Zhongyuan Du, Daiqin Bao, Yibo Zhao, Yu Zhu, Yue Wu, Xingnan Ouyang, Li Wang, Liangming Liu, Tao Li","doi":"10.7150/ijbs.136855","DOIUrl":"10.7150/ijbs.136855","url":null,"abstract":"<p><p>As important immune cells, macrophage polarization is directly related to tissue damage in sepsis, and the polarization of macrophages is associated with their metabolic patterns. Previous studies exploring macrophage function in sepsis mainly focused on specific tissues, lacking comprehensive comparisons between tissues. Herein, we performed single-cell RNA sequencing (scRNA-seq) to systematically profile macrophages derived from the brain, heart, intestine, lung, spleen, and peripheral blood mononuclear cells (PBMCs) under homeostatic and septic conditions. Under steady-state, we detected the markers of macrophages in different tissues, classified the macrophages into 10 functional subtypes and compared the differences in their distribution among tissues. In sepsis, we found that <i>Pkm2</i> and <i>Id2</i> played important roles in macrophage glycolysis. Mechanistically, <i>Id2</i> mediated the metabolic reprogramming of macrophages by regulating the chromatin accessibility of <i>Pkm2</i>. Helichrysetin, an inhibitor of <i>Id2</i>, could significantly alleviate tissue damage and increase the survival of septic mice. In summary, our research depicted a cross-tissue macrophage landscape at the single-cell level that encompasses both homeostasis and sepsis. We also provided a new target and a potential drug for the treatment of sepsis by inhibiting macrophage metabolic reprogramming.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7471-7486"},"PeriodicalIF":11.7,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891630","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":"Anlotinib enhances the sensitivity to docetaxel in lung cancer through inhibiting DDR1-mediated glycolytic pathway.","authors":"Xueqin Chen, Juan Shen, Zhifei Xu, Bo Xu, Jie Huang, Jingjing Jiang, Yidan Chen, Xin Li, Shaoyu Yang, Kan Wu, Jiaoli Wang, Peihua Luo, Qiaojun He, Shenglin Ma, Bing Xia, Bo Yang","doi":"10.7150/ijbs.129604","DOIUrl":"10.7150/ijbs.129604","url":null,"abstract":"<p><p>Discoidin domain receptor 1 (DDR1), a collagen-activated receptor tyrosine kinase, is essential for tumor cell proliferation, invasion and drug resistance. Our study demonstrated that the expression and phosphorylation of DDR1 were associated not only with the poor outcome of non-small cell lung cancer (NSCLC), but also with low sensitivity to docetaxel. Moreover, our kinase profiling identified that anlotinib, an oral small-molecule tyrosine kinase inhibitor, could significantly inhibit DDR1 phosphorylation. Further data revealed that anlotinib could increase the sensitivity to docetaxel in cell lines, cell-derived and patient-derived tumor xenografts through down-regulating DDR1 phosphorylation, which no longer existed in <i>DDR1</i>-KO A549 cells. Mechanistically, anlotinib could enhance the sensitivity to docetaxel through inhibiting DDR1-mediated glycolysis. Additionally, the clinical trial demonstrated that anlotinib could increase the efficacy of docetaxel, with an improved overall response rate of 35.6%, a prolonged median progression-free survival by 5.3 months and a median overall survival by 14.0 months compared with historical data. In summary, our study not only highlights the new function of DDR1 in energy metabolism but also provides further evidence for the combination of anlotinib and docetaxel as a preferable strategy in clinical practice.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"7610-7627"},"PeriodicalIF":11.7,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074560","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":"RNA Triple Helices: From Structures and Mechanisms to Therapeutic Targets.","authors":"Yiqi Ding, Zhechao Wang, Zimo Wu, Benyuan Cao, Haiyang Dong, Yongfeng Jin","doi":"10.7150/ijbs.132736","DOIUrl":"10.7150/ijbs.132736","url":null,"abstract":"<p><p>Major-groove RNA triple helices are conserved tertiary structures formed when a third strand inserts into the major groove of a classic double helix either via Hoogsteen base pairing or reverse Hoogsteen base pairing. These structures are widely distributed in eukaryotic, prokaryotic, and viral RNAs. This paper systematically summarizes the structural classification, stability-influencing factors, and identification methods of RNA triple helices. A growing body of evidence indicates that RNA triple helices are extensively involved in diverse biological processes, including RNA stability regulation, translation regulation, riboswitch ligand recognition, transposition regulation, telomerase activity, and the assembly of the spliceosome catalytic core, as well as serving as scaffolds for molecular recruitment. Notably, dysregulation of RNA triple helices is closely associated with tumorigenesis, viral infections, and genetic diseases. Based on their structural and functional characteristics, multiple therapeutic strategies targeting RNA triple helices have been explored, such as small molecules and antisense oligonucleotides. Collectively, RNA triple helices represent a pivotal link between RNA structural biology and precision medicine, with promising potential as an important candidate target for future RNA structural drug development.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7447-7470"},"PeriodicalIF":11.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13541005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891591","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":"DNAJB4 Protects Against Atherosclerosis by Stabilizing the HSP70-LXRα Axis in Hepatic Lipid Metabolism.","authors":"Wen-Hua Chen, Chia-Hui Chen, Man-Chen Hsu, Po-An Hu, Hsueh-Te Lee, Hsuan-Yun Hu, Kang-Yi Su, Wei-Lun Hsu, Tzong-Shyuan Lee","doi":"10.7150/ijbs.131807","DOIUrl":"10.7150/ijbs.131807","url":null,"abstract":"<p><p>DNAJB4, a member of the DNAJ/HSP40 family, functions as a co-chaperone of HSP70, regulating protein homeostasis and cellular functions. However, the molecular mechanism underlying the biological effect of DNAJB4 on lipid metabolism remains unclear. We investigated the role of DNAJB4 and its molecular mechanism in hyperlipidemia and atheroprone apolipoprotein E-null (<i>apoe^-/-</i> ) mice. Western blot analysis and immunohistochemistry were used to assess decreased DNAJB4 expression in <i>apoe^-/-</i> mice. Moreover, the genetic deletion of DNAJB4 led to an increase in hepatic lipid accumulation and hyperlipidemia in <i>apoe^-/-</i> mice, as evidenced by decreased expression of proteins related to cholesterol esterification and clearance, and an increased hepatic level of triglycerides, fatty acids, glycerol, free cholesterol, total cholesterol, and bile acid. Mechanistically, DNAJB4 deficiency impaired the protein stability of HSP70, reduced nuclear HSP70 association, and downregulated HSP70-induced LXRα transcription. The genetic deletion of DNAJB4 also promoted LXRα protein degradation and reduced LXRα autoregulation, thereby exacerbating the decrease in LXRα and LXRα-mediated gene expression. Furthermore, treatment with curcumin and andrographolide, the inducers of DNAJB4, did not reduce the atherosclerotic lesions at the aortic sinus in <i>apoe^-/-dnajb4^-/-</i> mice, suggesting that DNAJB4 is required for the atheroprotective effect of curcumin and andrographolide. Our findings indicate that DNAJB4 plays a crucial role in regulating the HSP70-LXRα axis in hyperlipidemia, hepatic lipid accumulation, and atherosclerosis. Here, we identify DNAJB4 as a critical HSP70 co-chaperone that stabilizes HSP70, promotes its nuclear association, and sustains LXRα autoregulation in hepatic lipid metabolism.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7380-7400"},"PeriodicalIF":11.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13541000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887154","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":"Artificial intelligence-assisted reinterpretation of preclinical progeria research suggests a hierarchical nuclear-vascular resilience framework with translational implications.","authors":"Paolo Madeddu, Monica Cattaneo, Annibale Alessandro Puca","doi":"10.7150/ijbs.133754","DOIUrl":"10.7150/ijbs.133754","url":null,"abstract":"<p><p>Preclinical research traditionally advances through hypothesis-driven experimentation that establishes mechanistic pathways to support translational development. While this approach has generated major biological insights, it may underemphasize alternative organizational patterns embedded within complex datasets, particularly in rare diseases where opportunities for experimental reiteration are limited. Recent advances in conversational artificial intelligence (AI) provide an opportunity to support structured analytical dialogue as a complementary approach for re-examining validated experimental observations. Here, we evaluated the feasibility and informative value of an investigator-led structured analytical dialogue to reinterpret a previously published preclinical study of Hutchinson-Gilford Progeria Syndrome (HGPS), a rare disorder characterized by accelerated cardiovascular aging. Investigators defined the analytical questions, established interpretative boundaries, and critically evaluated successive AI-generated outputs, while the AI platform functioned exclusively as an analytical support tool for exploring complementary conceptual organization of experimentally validated findings. The original study showed that delivery of the longevity-associated <i>LAV-BPIFB4</i> gene preserved left ventricular diastolic function, reduced perivascular fibrosis, increased coronary arteriole density, and attenuated cellular senescence without modifying progerin accumulation. Structured analytical dialogue generated complementary hierarchical interpretations of these observations. By integrating graphical dispersion with individual-level numerical data, the investigator-led dialogue identified heterogeneous response trajectories and suggested that cardiovascular protection may be viewed as emerging from coordinated interactions between nuclear stress adaptation and vascular remodelling within a broader resilience framework. These interpretations are presented as hypothesis-generating conceptual extensions rather than new experimental findings. This study demonstrates the feasibility of structured investigator-led analytical dialogue as a complementary methodological approach for broadening interpretation of existing preclinical datasets while preserving the original experimental evidence. By making analytical reasoning more transparent and explicitly distinguishing validated observations from conceptual reinterpretation, this framework may assist prioritization of future mechanistic investigations, particularly in rare cardiovascular diseases where maximizing insight from existing datasets is especially important.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7349-7357"},"PeriodicalIF":11.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887105","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":"FOXP3 Stability-Adaptation Paradox: Reshaping Treg-Based Therapies for Intestinal Diseases.","authors":"Yushuo Ren, Xiaohui Liu, Boya Wang, Haoyuan Yin, Jiatong Zhao, Shuzi Xin, Hongli Wang, Yuchen Zhang, Xinyue Liu, Jingyu Liu, Rongxuan Hua, Xiang Tian, Yuhang Bian, Sijin Gu, Haoxuan Zhang, Tong Wei, Lei Gao, Xin Lu, Hongwei Shang, Han Gao, Jingdong Xu","doi":"10.7150/ijbs.137066","DOIUrl":"10.7150/ijbs.137066","url":null,"abstract":"<p><p>Regulatory T cells (Tregs) maintain intestinal immune homeostasis, but their therapeutic potential is constrained by a fundamental paradox: the same plasticity that enables tissue repair renders FOXP3 vulnerable to degradation in chronic inflammation. Mechanistically, microbial metabolites (short-chain fatty acids, bile acids) and retinoic acid stabilize FOXP3 and induce RORγt⁺/GATA3⁺ Treg specialization. In contrast, inflammatory cytokines and succinate accumulation drive ER stress and post-translational FOXP3 degradation, leading to lineage instability in inflammatory bowel disease, colorectal cancer, and celiac disease. Current Tregs-based therapies-adoptive transfer, low-dose IL-2, CAR-Tregs, and microbiota consortia-have demonstrated safety profiles yet exhibit limited efficacy due to this inherent instability. Next-generation strategies therefore focus on actively stabilizing FOXP3 (e.g., gut-restricted HDAC inhibitors) and engineering exhaustion-resistant CAR-Tregs. Three questions remain for clinical translation: how to preserve Treg stability without compromising anti-tumor immunity; which biomarkers (succinate, TSDR methylation, FOXP3Δ2/FL ratio) predict response; and whether logic-gated CAR-Tregs can overcome exhaustion. Addressing these challenges will enable the development of precision Treg immunotherapy for intestinal diseases.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7401-7426"},"PeriodicalIF":11.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13541010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887120","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}