International Journal of Biological Sciences最新文献

{"title":"Epigenetic orchestration of RNA m⁶A methylation in wound healing and post-wound events.","authors":"Heao Zhang, Delong Gao, Zixin Li, Sis Aghayants, Yiping Wu, Zeming Liu, Qi Zhang","doi":"10.7150/ijbs.114988","DOIUrl":"https://doi.org/10.7150/ijbs.114988","url":null,"abstract":"<p><p>Skin, the largest human organ, demonstrates remarkable regenerative capacity through spatiotemporally coordinated healing processes. Chronic wounds, including diabetic ulcers and burn injuries pose significant clinical challenges due to persistent inflammation, impaired angiogenesis, defective appendage regeneration, and pathological scarring. Emerging evidence reveals N⁶-methyladenosine (m⁶A) methylation - the most prevalent RNA modification - as a critical regulator of wound healing and tissue remodeling. The m⁶A machinery (writers, readers, erasers) dynamically controls RNA stability, translation, and splicing, thereby modulating keratinocyte migration, fibroblast activation, macrophage polarization, and stem cell differentiation. Dysregulated m⁶A dynamics impair diabetic wound healing through oxidative stress amplification and autophagy deficiency, while disrupting critical repair pathways in burn injuries. Aberrant m⁶A modifications exacerbate pathological scarring and dysfunctional appendage regeneration via dysregulated extracellular matrix deposition and fibroblast dysfunction. Current understanding of m⁶A spatiotemporal regulation and clinical potential remains fragmented despite significant advances. Future investigations integrating single-cell sequencing, spatial transcriptomics, and multidisciplinary approaches are crucial to decode the multifaceted roles of m⁶A, enabling the development of novel epitranscriptome-targeted therapies for chronic wound management and functional skin regeneration. The review systematically examines m⁶A-mediated mechanisms in cutaneous repair and remodeling, providing strategic insights for advancing regenerative medicine.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 11","pages":"4927-4941"},"PeriodicalIF":10.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953133","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":"N4-acetylcytidine modification of LINC02802 promotes non-small cell lung cancer progression by modulating mitochondrial NAD+/NADH ratio.","authors":"Yixiao Yuan, Dahang Zhang, Juan Wang, Lin Tang, Yaowu Duan, Lincan Duan, Xiulin Jiang","doi":"10.7150/ijbs.116639","DOIUrl":"https://doi.org/10.7150/ijbs.116639","url":null,"abstract":"<p><p>Long non-coding RNAs (lncRNAs) have emerged as key regulators of cancer progression through their interaction with microRNAs and modulation of gene expression. However, their role in mitochondrial metabolism, particularly in non-small cell lung cancer (NSCLC), remains poorly defined. In this study, we found that LINC02802 was significantly upregulated in NSCLC tissues and associated with poor prognosis. Mechanistically, LINC02802 acts as a competing endogenous RNA (ceRNA) for miR-1976, thereby relieving the suppression of solute carrier family 25 member 51(SLC25A51). Elevated SLC25A51 enhances mitochondrial NAD⁺ import, leading to an increased NAD⁺/NADH ratio and promoting oxidative TCA cycle flux. Functionally, this shift supports tumor cell proliferation and migration. Rescue experiments confirmed that the oncogenic effect of LINC02802 is dependent on the miR-1976/SLC25A51 axis. Interestingly, either silencing LINC02802 with antisense oligonucleotides (ASOs) or treating cells with fludarabine phosphate, an SLC25A51 inhibitor, successfully reversed cisplatin resistance in lung cancer cells. Our findings reveal a novel lncRNA-microRNA-metabolic axis wherein LINC02802 facilitates NSCLC progression by reprogramming mitochondrial metabolism via miR-1976-mediated upregulation of SLC25A51. Targeting this axis may offer therapeutic potential for metabolic intervention in NSCLC.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 11","pages":"4908-4926"},"PeriodicalIF":10.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953223","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":"Citrus Pectin Supplementation Alleviated Hepatic Lipid Accumulation through Gut Microbiota Indole Lactic Acid Promoting Hepatic Bile Acid Synthesis and Excretion.","authors":"Zhijun Pan, Xinyuan Jin, Qing Li, Yuqing Zhou, Yupeng Zeng, Xin Wang, Yufeng Jin, Yu Chen, Dan Li, Wenhua Ling","doi":"10.7150/ijbs.116929","DOIUrl":"https://doi.org/10.7150/ijbs.116929","url":null,"abstract":"<p><p>Metabolic-associated fatty liver disease (MAFLD) represents a critical global health challenge. A few studies have suggested that citrus pectin may confer protective effects against MAFLD; however, the underlying mechanism remains unclear. The gut microbiota and its metabolites strongly contribute to MAFLD regulation by the gut‒liver axis. The present study explored the influence of pectin intervention on liver lipid accumulation in high-fat and high-sugar diet-fed mouse models. Pectin supplementation alleviated hepatic lipid accumulation and substantially restructured the gut microbial communities, particularly enhancing the proliferation of <i>Akkermansia muciniphila</i> (<i>A. muciniphila</i>) and <i>Escherichia coli</i> (<i>E. coli</i>), which subsequently increased indole-3-lactic acid (ILA) production. Mechanistic investigations revealed that ILA upregulated hepatic CYP7A1 and FXR-BSEP expression, stimulating hepatic bile acid biosynthesis and biliary excretion to alleviate liver steatosis. Results of previous fecal microbiota transplantation (FMT) and antibiotic-mediated microbial dysbiosis studies have confirmed the microbiota-dependent nature of the therapeutic effects of pectin. Furthermore, the administration of exogenous ILA has been demonstrated to be an effective intervention for the rescue of metabolic dysregulation in dysbacteriosis mouse models. This work delineated an unrecognized dietary pectin-microbiota-ILA-hepatic bile acid synthesis and excretion regulatory axis for the improvement of MAFLD.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 11","pages":"5015-5033"},"PeriodicalIF":10.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953095","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":"Blocking interplay between TERT and c-Myc: a new therapeutic strategy for <i>BRAF^V600E/pTERT</i> double mutated tumors.","authors":"Jing Wei, Jiazhe Liu, Yan Zhang, Guobin Wang, Xiao Cui, Wei Yu, Chunlei Nie, Peng Hou","doi":"10.7150/ijbs.111224","DOIUrl":"https://doi.org/10.7150/ijbs.111224","url":null,"abstract":"<p><p>Tumors with coexisting mutations of <i>BRAF^V600E</i> and <i>TERT</i> promoter (<i>pTERT</i>) are more aggressive and associated with poor patient survival. However, the effective treatments for these tumors are limited, and the mutual regulation mechanism between these two molecules remains largely unclear. Here, we demonstrated that BRAF and TERT could mutually regulate each other, and c-Myc played a vital role in this process. Mechanistically, c-Myc could promote <i>BRAF</i> transcription<i>,</i> and TERT interacted with and stabilized c-Myc. Meanwhile, we verified that c-Myc transcriptionally repressed <i>PP2Ac</i>, which, as the core catalytic subunit of PP2A, leads to dephosphorylation of c-Myc at Ser62, decreasing its stability. These molecular events promoted the progression of <i>BRAF^V600E/pTERT</i> double mutated tumors by forming positive regulatory networks. To develop therapeutic strategy for this kind of tumors, we designed two peptides p-CPS62 and CPS62 to break the interaction between TERT and c-Myc, and constructed the corresponding aurous nanoparticles (AuNP-p-CPS62 and AuNP-CPS62). The results showed that AuNP-p-CPS62 and AuNP-CPS62, especially the former, effectively suppressed the growth of <i>BRAF^V600E/pTERT</i> double mutated cancer cells both <i>in vitro</i> and <i>vivo</i>, with good biosafety. These findings suggest that blocking the interaction between TERT and c-Myc may be a promising therapeutic option for <i>BRAF^V600E/pTERT</i> double mutated tumors.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 11","pages":"4961-4978"},"PeriodicalIF":10.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952913","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":"Ferroptosis-Resistant Adipocytes Drive Keloid Pathogenesis via GPX4-Mediated Adipocyte-Mesenchymal Transition and Iron-Cystine Metabolic Communication.","authors":"Xiangguang Shi, Xueyi Xia, Yang Xiao, Huizhen Shu, Zhuoya Xu, Mengguo Liu, Chenyi Shi, Ying Zhang, Yining Wei, Yiyi Gong, Wei Wang, Yahui Chen, Jianlan Liu, Jia Huang, Mengkun Shi, Jiucun Wang, Wenyu Wu","doi":"10.7150/ijbs.114930","DOIUrl":"https://doi.org/10.7150/ijbs.114930","url":null,"abstract":"<p><p><b>Background:</b> Keloids are a challenging fibrotic disorder with limited treatment options. The study sought to examine the underlying mechanisms of keloid pathogenesis, emphasizing the influence of dermal adipocytes and ferroptosis resistance in driving fibrosis. <b>Methods:</b> Single-cell RNA sequencing (scRNA-seq) was employed for determining essential cell populations in keloid tissue. Mechanistic studies assessed iron overload, Reactive Oxygen Species (ROS) exhaustion, and interferon responses in ferroptosis-resistant adipocytes. Glutathione peroxidase 4 (GPX4) expression and TGF-β signaling activation were evaluated in adipocyte-mesenchymal transition (AMT). Paracrine signaling and metabolic symbiosis between adipocytes and fibroblasts were analyzed. Therapeutic interventions (ferroptosis inducer RSL3 and iron chelator deferoxamine DFO) were tested <i>in vivo</i>. <b>Results:</b> Through single-cell RNA sequencing, we identified ferroptosis-resistant dermal adipocytes as key contributors to keloid pathogenesis, exhibiting iron overload, ROS suppression, and impaired interferon responses. These adipocytes demonstrated elevated GPX4 expression, which mechanistically drove AMT via iron-dependent activation of TGF-β signaling pathways. GPX4-activated adipocytes promoted fibroblast collagen production through paracrine signaling while establishing a metabolic symbiosis: adipocytes exported iron via solute carrier family 40 member 1 (SLC40A1) to neighboring fibroblasts, which reciprocally supplied cystine through cystathionine beta-synthase (CBS)/cystinosin, lysosomal cystine transporter (CTNS) to sustain GPX4 activity. This vicious cycle was further amplified by iron/ROS-mediated suppression of interferon signaling, creating a pro-fibrotic feedback loop. Therapeutic targeting with either the ferroptosis inducer RSL3 or iron chelator deferoxamine (DFO) effectively disrupted this pathological network, suppressing GPX4/AMT while restoring interferon responses and attenuating keloid growth <i>in vivo</i>. This study clarifies a new adipocyte-focused mechanism in keloid development and identifies ferroptosis regulation as a potential treatment approach for this persistent condition. Conclusions: This study reveals a novel adipocyte-centered mechanism in keloid pathogenesis driven by GPX4-mediated ferroptosis resistance, metabolic symbiosis, and disrupted interferon signaling<b>.</b> The findings establish ferroptosis modulation (via RSL3 or iron chelation) as a promising therapeutic strategy for keloids, offering potential new treatments for this recalcitrant condition.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 11","pages":"5097-5115"},"PeriodicalIF":10.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953146","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":"siRNA as a criterion in host immunity and cancer immunotherapy: modulating factors and nano-conjugate based approach for intervention.","authors":"Rahul Bhattacharjee, Debanjan Das, Srija Chakraborty, Radheka Bhaduri, Soham Chattopadhyay, Rajeev K Singla, Vinoth Kumarasamy, Rohit Gundamaraju","doi":"10.7150/ijbs.109637","DOIUrl":"https://doi.org/10.7150/ijbs.109637","url":null,"abstract":"<p><p>The use of Small interfering RNAs (siRNA) is prevalent in various cancer-based therapies. siRNA is a powerful RNAi, which can be used in clinical oncology with nanoparticles as a vector for delivery. A nano-based siRNA conjugated system has been used to target various multi-drug resistance (MDR) genes of cancer to increase therapeutic specificity and control tumor progression using effective delivery. It offers a targeted avenue in gene silencing with reduced off-target effects. Pre-clinical studies show the effectiveness of this combined siRNA-nanoconjugates therapy in chemotherapeutics resistance to cancer cells. This combinatorial approach not only has the potential to induce an immune response inside the host cells but also renders the MDR genes of various cancers ineffective. The current review focuses on the effect of siRNA entry on immune cells and the factors governing them. Moreover, we have further discussed the limiting factor that controls the siRNA-nanoconjugates efficiency for effective tumor regression. We have enumerated the preclinical and clinical significance of this combined therapy for enhanced tumor regression. Furthermore, we have elaborated the impact of this combined nano-conjugated therapy host immune system while pointing out the limitations posed by them. Thus, in essence, this review provides a unique platform for the readers to understand the potential of siRNA-conjugates for anti-cancer therapy from pre-clinical to bench side.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 11","pages":"5116-5134"},"PeriodicalIF":10.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953204","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":"PLK4 as a Key Regulator of Neuroblastoma Differentiation and a Promising Therapeutic Target.","authors":"Xiangdong Tian, Yuren Xia, Wenchen Gong, Kangwei Zhu, Yulong Yang, Zhiqiang Han, Yun Liu, Jie Li, Xin Li, Yuchao He, Mingyou Gao, Lu Chen, Hua Guo, Qiang Zhao","doi":"10.7150/ijbs.111449","DOIUrl":"https://doi.org/10.7150/ijbs.111449","url":null,"abstract":"<p><p><b>Background:</b> Neuroblastoma (NB) differentiation status critically influences prognosis and treatment response. Although differentiation therapy has shown clinical benefit, its efficacy remains limited. The molecular mechanisms driving NB differentiation are not fully understood. PLK4 has been linked to NB tumorigenesis, but its role in regulating differentiation remains unclear. <b>Methods:</b> We investigated the role of PLK4 in neuroblastoma differentiation by modulating its expression both <i>in vitro</i> and <i>in vivo</i>. Through comprehensive analyses employing Western blotting, co-immunoprecipitation, immunofluorescence and murine neuroblastoma models, we identified downstream signaling pathways involved in PLK4-mediated regulation of neuronal genes. Pharmacological inhibition of PLK4 further confirmed its functional relevance in promoting neuroblastoma differentiation. <b>Results:</b> PLK4 functions as a key regulator of neuroblastoma differentiation. Its depletion enhances neuronal maturation and sensitizes cells to 13-<i>cis</i> RA. Mechanistically, we identify a novel PLK4-CXCR4 signaling axis that governs neuroblastoma differentiation through PI3K/Akt-mediated modulation of cyclin D1 expression. The selective PLK4 inhibitor CFI-400945 exhibits dual anti-tumor activity by promoting terminal differentiation and suppressing proliferation. <b>Conclusions:</b> Our study identifies PLK4 as a potential molecular switch governing NB differentiation and a promising therapeutic target to overcome resistance to 13-<i>cis</i> RA.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 11","pages":"4979-4996"},"PeriodicalIF":10.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953266","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":"A Small Molecule Selectively Targets N-Myc to Suppress Neuroblastoma Cancer Progression.","authors":"Ying Miao, Huang Chen, Yuzhan Li, Liting Li, Jiangnan Ye, Jingwen Zhang, Jiayu Wang, Haigang Wu, Guihong Li, Yihua Chen, Zhengfang Yi, Mingyao Liu","doi":"10.7150/ijbs.97195","DOIUrl":"https://doi.org/10.7150/ijbs.97195","url":null,"abstract":"<p><p>Neuroblastoma, a prevalent and lethal extracranial solid tumor in childhood, remains a significant challenge in pediatric oncology worldwide. High-risk neuroblastoma (HR-NB) is particularly aggressive and linked to a poor prognosis due to the limited availability of effective treatments. The aberrant amplification of the <i>MYCN</i> gene is a critical genetic alteration observed in neuroblastoma conferring poorer clinical outcomes. To date, no drugs targeting N-Myc have been approved. In this study, we successfully established a novel high-throughput screening system targeting N-Myc and identified the first small molecule inhibitor, N78, which exhibits selective, high affinity for N-Myc over c-Myc. N78 selectively degrades N-Myc, suppresses the expression of its target genes, and effectively diminishes the viability of <i>MYCN</i>-dependent tumor cells. Notably, N78 demonstrates acceptable tolerability and induces significantly enhanced tumor regression <i>in vivo</i> compared to Myci975, a leading candidate among c-Myc/N-Myc inhibitors. Mechanistically, N78 promotes the phosphorylation of N-Myc at threonine-58, leading to its degradation via the ubiquitin-proteasomal pathway. This study presents the first selective N-Myc inhibitor N78, and highlights the promise of small-molecule N-Myc inhibitors as both chemical probes and potential anti-cancer therapies for neuroblastoma.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 11","pages":"4895-4907"},"PeriodicalIF":10.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952958","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":"Innate Immunity Reimagined: Metabolic Reprogramming as a Gateway to Novel Therapeutics.","authors":"Chuan-Han Deng, Chen-Tong Wang, Xin Zhou, Xin Chen, Ying Wang","doi":"10.7150/ijbs.114010","DOIUrl":"https://doi.org/10.7150/ijbs.114010","url":null,"abstract":"<p><p>The interplay between cellular metabolism and innate immunity critically shapes the body's ability to fight infections, repair tissue, and manage stress. Metabolic reprogramming not only drives innate immune activation but also regulates the resolution of inflammation. Phenotypes of immune cell are closely linked to metabolic shifts that adapt to varying energy demands. However, the precise relationship between perturbations in the cellular respiratory-metabolic axis and the inflammatory response remains a critical field of investigation. In depth understanding of key metabolic pathways, such as glycolysis, NADPH oxidase activity, mitochondrial ROS production, TCA cycle metabolites, and cGAS-STING/AIM2 inflammasome activation, is essential to unravel the complexities of innate immunity. This article highlights the central role of metabolic reprogramming mainly in innate immunity and explores its potential as a therapeutic target for modulating inflammatory response.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 11","pages":"5056-5078"},"PeriodicalIF":10.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953111","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 the NAT10/XIST/YAP1 Axis-Mediated Vascular Abnormalization Enhances Immune Checkpoint Blockade in Gastric Cancer.","authors":"Xuetao Lei, Boyang Zheng, Yanmei Peng, Guofan Zhang, Xia Cheng, Wenqiang Li, Jiayong He, Fengping Li, Ruoyu Ling, Ziyi Fu, Qingbin Yang, Gengtai Ye, Guoxin Li","doi":"10.7150/ijbs.113325","DOIUrl":"https://doi.org/10.7150/ijbs.113325","url":null,"abstract":"<p><p>Tumor vascular normalization has emerged as a promising strategy to potentiate immune checkpoint blockade in solid tumors. Here, we unveil a previously unrecognized NAT10/XIST/YAP1/VEGFA signaling axis driving vascular abnormalization in gastric cancer (GC) and demonstrate its therapeutic potential in remodeling the tumor immune microenvironment. Through integrative analysis of acetylated RNA immunoprecipitation sequencing (acRIP-seq) and functional validation, we identified NAT10-mediated N4-acetylcytidine (ac4C) modification as a critical stabilizer of lncRNA XIST. Mechanistically, XIST recruits hnRNPK to facilitate YAP1 nuclear translocation, thereby activating TEAD4-dependent VEGFA transcription and promoting angiogenic programming. Genetic or pharmacological inhibition of NAT10 with Remodelin attenuated VEGFA secretion, enhanced pericyte coverage and basement membrane integrity, and normalized tumor vasculature in syngeneic GC models. Moreover, we found that NAT10 inhibition reshaped the immune landscape by upregulating CXCL9/10/11 chemokines, promoting cytotoxic lymphocyte infiltration while reducing Treg populations. Strikingly, combining Remodelin with the YAP1 inhibitor Verteporfin synergistically augmented anti-PD-1 efficacy, significantly suppressing tumor growth in immunocompetent mouse models. Our findings not only elucidate an ac4C-dependent epitranscriptomic mechanism governing vascular-immune crosstalk but also propose a novel combinatorial therapeutic strategy to overcome resistance to immune checkpoint blockade in GC.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 11","pages":"4997-5014"},"PeriodicalIF":10.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953212","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}