International Journal of Biological Sciences最新文献

{"title":"<i>HOTAIR</i> Promotes Prostate Cancer Progression by facilitating CDK9-Pol II Association and Transcriptional Elongation.","authors":"Yuyang Qian, Bo Wang, Guangsong Su, Peng Li, Zhenhao Zhao, Yuan Jiang, Lei Zhang, Zhongfang Zhao, Mulin Jun Li, Jiandang Shi, Dandan Huang, Wange Lu","doi":"10.7150/ijbs.134766","DOIUrl":"10.7150/ijbs.134766","url":null,"abstract":"<p><p>Previous research has predominantly focused on the regulatory role of lncRNA <i>HOTAIR</i> in gene silencing by interacting with the Polycomb repressive complex 2 (PRC2), but its direct role as a transcriptional activator remains less well characterized. Here, our study reveals a novel regulatory mechanism of <i>HOTAIR</i>, which facilitates prostate cancer (PCa) progression by enhancing transcription elongation. Integrating ChIRP-seq, RNA-seq, and ChIP-seq, we found that HOTAIR co-localizes with AR and facilitates the interaction between CDK9 and Pol II. This function requires the 1-442 nt region and intact RNA, as deletion or RNase treatment disrupts the interaction. Re-expression of full-length HOTAIR, but not the deletion mutant, restores nascent transcription of target genes; conversely, CDK9 inhibition suppresses this elongation effect. We identified <i>MMP14</i> and <i>TNFAIP2</i> as functional downstream targets; ectopic expression of either rescues colony formation and invasive migration upon <i>HOTAIR</i> depletion. <i>HOTAIR</i> knockdown reduced Ser2P and Ser5P signals at target loci, yet RNA pull-down showed no direct binding to Pol II Ser5P, implying that any effect on initiation is indirect. This elongation activity operates in both AR-positive and AR-negative cells, with AR acting as a context-specific recruiter. Collectively, these findings support a model in which <i>HOTAIR</i> functions as an elongation activator and suggest potential therapeutic targets in prostate cancer.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"8054-8073"},"PeriodicalIF":11.7,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074619","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":"Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer.","authors":"Sicheng Bian, Huiqin Bian, Hiroaki Koyama, Dmytro Kompaniiets, William Tse, Mithun V Shah, Aref Al-Kali, Alexander Miron, Bin Liu, Shujun Liu","doi":"10.7150/ijbs.131687","DOIUrl":"https://doi.org/10.7150/ijbs.131687","url":null,"abstract":"<p><p>Although multi-hit TP53 mutations correlate with rapid disease progression, treatment resistance, recurrence, and poor survival, their occurrence within an individual TP53 gene molecule (cbTP53) remains unexplored. Consequently, the impact of cbTP53 on protein conformation, transcriptional architecture, and oncogenicity is unknown. We show that cbTP53 with combined mutations (Y220C+R248Q+R282Q) does not drastically alter local stability or structural conformation, but significantly affects TP53 binding to DNA promoters comparing it to a single Y220C mutation. Functionally, cbTP53 promotes divergent cellular phenotypes, characterized by enhanced cell proliferation, increased formation of multicellular tumor spheroids (MCTS) and spheroids, altered responses to chemotherapeutic drugs (e.g., cisplatin, carboplatin) and p53 inhibitors (e.g., MB710, PK11007), and increased resistance to carboplatin-induced DNA damage. Furthermore, cbTP53 is linked to distinct immune cell profiles (e.g., CD4+ and CD8+ T cells, nature killer cells, dendritic cells), more circulating tumor cells, a higher rate of tumor engraftment, and an increased number of lung tumor nodules. Mechanistically, introduction of R248Q/R282Q mutations changes 42.7% of Y220C-regulated gene expression, and cbTP53 (vs Y220C) owns a distinctive transcriptomic signature with 1,004 up- and 1,747 down-regulated genes. cbTP53 shows the enhanced binding affinity in the promoters of inflammatory cytokines, leading to their increased production. This study establishes causative and mechanistic links of cbTP53 to lung aggressive cancer metastasis and disease progression, providing a novel perspective on the genetics of TP53 mutations in cancer.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 15","pages":"8139-8157"},"PeriodicalIF":11.7,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13685541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149244202","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":"Spatial, single-nucleus and pathological profiling of the invasive front in early hepatocellular carcinoma for characterizing specific leading-edge cell niche and improving recurrence modeling.","authors":"Xicheng Wang, Xiaolan Mu, Yong Fu, Wei Dong, Wenfeng Lu, Xiuhua Li, Yanxiang Song, Changcheng Liu, Baoju Hou, Haibin Zhang, Xiong Chen, Yongchao Cai, Zhiying He","doi":"10.7150/ijbs.137262","DOIUrl":"10.7150/ijbs.137262","url":null,"abstract":"<p><p>The tumor leading edge (TLE) is a critical region where tumor cells interact with the microenvironment to drive invasion and metastasis; however, its cellular architecture in early hepatocellular carcinoma (HCC) remains poorly understood. Here, we integrated single-nucleus RNA-seq (snRNA-seq), spatial transcriptomics, and computational pathology to investigate TLE in early HCC. We annotated 35 cell subpopulations and identified STMN1-high tumor cells as a key malignant subset enriched at the invasive front, interacting with Treg, plasma B, LAMP3⁺ dendritic cells and SPP1⁺ macrophages. Spatial analysis revealed three co-localized cell pairs-(SPP1⁺ macrophages co-localized with Tip-like and inflammatory endothelial cells), (LAMP3⁺ DCs co-localized with naive T cells), and (plasma B cells co-localized with cancer-associated fibroblasts)-forming a leading-edge tumor microenvironment (L-TME) niche associated with early relapse. We developed an L-TME-related machine-learning benchmark framework incorporating 71 imaging features (65 deep-learning + 6 pathological) based on the snRNA-seq, spatial transcriptomics and pathomics. The pathology model achieved robust performance (mean C-index=0.77) and successfully predicted the recurrence of early HCC (log-rank <i>p</i> < 0.05) in TCGA (n=147) and an independent in-house cohort (n=123). This study delineates the TLE cellular ecosystem of early HCC, defines a spatially coordinated immunosuppressive L-TME niche, and provides a clinically applicable predictive tool for postoperative recurrence. Integrating multi-omics with computational pathology deepens our understanding of early HCC metastasis and offers insights into improved prognostication and therapeutic strategies.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"8090-8118"},"PeriodicalIF":11.7,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074514","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":"Disrupted Estrogen Homeostasis Drives Female-Specific Depressive-Like and Anxiety-Like Behaviors via Convergent ERα Downregulation in the Ventral Hippocampus.","authors":"Zhengyang Wang, Yikun Ren, Feiran Cheng, Peng Wang, Bangmin Yin, Yajie Xiang, Ying Yu, Dan Liu, Xinyi Yang, Peng Xie","doi":"10.7150/ijbs.137575","DOIUrl":"10.7150/ijbs.137575","url":null,"abstract":"<p><p>Although depression exhibits prominent sex differences, mechanisms linking estrogen fluctuations to this vulnerability remain unclear. Here, we reveal that disrupted estrogen homeostasis induces depressive- and anxiety-like behaviors via convergent downregulation of estrogen receptor alpha (ERα) and subsequent neuroinflammation in the female ventral hippocampus (vHPC). In humans (n=6,481), serum estradiol (E2) showed a U-shaped association with depression, increasing risk at both extremes. In mice, while chronic restraint stress (CRS) induced depressive-like behaviors across sexes, it selectively triggered E2 deficiency, anxiety-like behaviors, and decreased vHPC ERα (but not ERβ) in females. Therefore, focusing on females, both supraphysiological E2 (sE2)-induced elevation and CRS-induced E2 deficiency produced depressive- and anxiety-like behaviors converging on vHPC ERα downregulation. Cross-species transcriptomics and multi-omics revealed global concordance between female major depressive disorder (MDD) and both mouse models, identifying ERα as a top upstream regulator associated with neuroinflammation, lipid dysregulation, and synaptic dysfunction. Pharmacological inhibition of ERα exacerbated depressive- and anxiety-like behaviors and neuroinflammation under subthreshold CRS, whereas vHPC ERα overexpression rescued CRS-induced behavioral deficits and neuroinflammatory responses. Integrating human MDD GWAS and PsyGeNET datasets supported this pathway's genetic and clinical relevance. Collectively, we identify vHPC ERα as a unifying therapeutic target for female depression.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"8074-8089"},"PeriodicalIF":11.7,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074652","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":"USP10 stabilizes FOXM1 through KAT5-mediated acetylation to suppress cell senescence and promote melanoma malignant progression.","authors":"Zhiyuan Qiu, Chenglian Sun, Juan Wang, Dapeng Liang, Shang Wang, Lili Tian, Tongde Du, Chuanchun Han","doi":"10.7150/ijbs.136120","DOIUrl":"10.7150/ijbs.136120","url":null,"abstract":"<p><p>The ubiquitin signaling cascade plays a pivotal role in multiple cancer types, yet its role in melanoma progression remains incompletely elucidated. An unbiased and systematic analysis indicates that Ubiquitin-specific peptidase 10 (USP10), a member of USP gene family, was top priority prognostic signature for primary and metastatic melanoma progression-free survival and silencing USP10 markedly impairs the growth and metastatic potential of melanoma cells. We further uncover Forkhead box M1 (FOXM1) as a novel substrate of USP10. USP10 directly binds to FOXM1 and removes ubiquitin chains, thereby enhancing FOXM1 protein stability and driving melanoma progression. Notably, the lysine acetyltransferase KAT5 acetylates FOXM1 at residues K422 and K440, which strengthens the interaction between FOXM1 and USP10, facilitating deubiquitination and subsequent stabilization of FOXM1. Additionally, loss of either USP10 or FOXM1 suppresses the expression of the downstream target Telomerase reverse transcriptase (TERT), triggering cellular senescence. Importantly, we identify Golvatinib, as a novel inhibitor of USP10 that effectively curbs melanoma malignancy in both cellular and animal models. Taken together, these findings highlight the pro-tumorigenic role of USP10 in melanoma and suggest that disrupting the USP10/FOXM1 signaling axis could represent a viable therapeutic approach for treating this aggressive cancer.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"8029-8052"},"PeriodicalIF":11.7,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074549","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":"ZIP1-dependent lymphatic adaptations facilitate lymph node metastasis of pancreatic cancer.","authors":"Ruoyang Chen, Kaili Zhang, Jiajia Wan, Yuanyuan Yang, Linlin Wang, Xiangjing Miao, Qingqing Fang, Yu Hu, Xixi Duan, Xiaohan Lou, Xiaohan Yao, Anqi Li, Linyu Zhu, Zhihai Qin, Chen Ni","doi":"10.7150/ijbs.134874","DOIUrl":"10.7150/ijbs.134874","url":null,"abstract":"<p><p>Tumor disseminates through lymphatic vessels to form lymph node (LN) metastasis, which requires lymphatic adaptations. However, it remains largely unknown how lymphatic vessels adapt to the stimuli causing LN metastasis of pancreatic cancer. Zinc dyshomeostasis has been observed in various tumors, including pancreatic cancer. We hypothesize that lymphatic vessels actively adapt to zinc imbalance, and examine lymphatic functions and LN metastasis of transplanted pancreatic cancer in zinc transporter ZIP1 deficient mice. The results show that ZIP1 is required for lymphatic glycolysis and junctional adaptations that facilitate LN metastasis of pancreatic cancer. In <i>Zip1^-/-</i> mice, the opening of lymphatic barrier and LN metastasis of pancreatic cancer are both mitigated. Inhibition of ZIP1 decreases Zn²⁺ influx and increases tight junction protein Claudin-5 in lymphatic endothelial cells, thereby suppressing tumor trans-endothelial migration. Mechanistically, ZIP1 promotes lymphatic glycolysis to produce lactic acids which impair Claudin-5 expression. Furthermore, in lymphatic-specific <i>Zip1</i> knockout mice, lymphatic barrier is tightened and LN metastases are reduced. Importantly, ZIP1⁺ lymphatics are positively associated with LN metastasis of human pancreatic cancer. Taken together, these findings suggest that ZIP1-dependent metabolic and junctional adaptations in lymphatics accelerate LN metastasis of pancreatic cancer, providing potential therapeutic targets for pancreatic cancer metastasis.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"8119-8138"},"PeriodicalIF":11.7,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074461","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":"LDHA Lactylation Drives Malignant Progression of Oral Squamous Cell Carcinoma via a Positive Feedback Loop with Lactate.","authors":"Fan Song, Chen Hou, Yingzhao Huang, Hongshi Cai, Jianfeng Liang, Yaoqi Jiang, Qiong Xu, Jinsong Hou","doi":"10.7150/ijbs.136949","DOIUrl":"https://doi.org/10.7150/ijbs.136949","url":null,"abstract":"<p><p>Lysine lactylation (Kla) is an emerging post-translational modification closely linked to glycolysis, where it functions to regulate the activity of glycolytic enzymes. In oral squamous cell carcinoma (OSCC), elevated expression of Lactate dehydrogenase A (LDHA) drives lactate production, thereby supplying the substrate for Kla. Nevertheless, whether LDHA itself undergoes Kla in OSCC has yet to be explored. Here, we have conclusively verified that LDHA undergoes high-level Kla in OSCC tissues and cells, with its Kla abundance positively associated with intracellular lactate concentrations. Both <i>in vitro</i> and <i>in vivo</i> analyses collectively illustrated that LDHA-K318 lactylation functions as a crucial driver of OSCC malignant progression. Functionally, our investigations revealed that the LDHA-K318R mutation diminishes lactate generation and decreases global protein Kla levels. GCN5 acts as an upstream \"writer\" that coordinately regulates LDHA-Kla, thereby modulating lactate production and facilitating OSCC malignancy. Furthermore, we identified HDAC1 as an \"eraser\" that governs LDHA-Kla status. Combined administration of the GCN5 inhibitor MB-3 and the LDHA-K318 lactylation-targeting peptide (K318-pe) remarkably inhibited tumor growth in the PDX models. Our study uncovers a positive feedback loop linking lactate and glycolysis, mediated by LDHA-Kla in OSCC. This discovery implicates lactylation-associated regulators as viable therapeutic targets, opening novel perspectives for clinical application.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 15","pages":"8193-8209"},"PeriodicalIF":11.7,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13685604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149244325","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":"Triptolide in Combination with the Gli1 Inhibitor GANT61 Eradicates Anaplastic Thyroid Cancer by Suppressing Cancer Stem Cell Self-Renewal and Enhancing Apoptosis and Pyroptosis.","authors":"Yuqing Zhao, Yue Zhu, Shuying Zhong, Penggang Liu, Wei Li, Xiaoyun Mao, Xiulong Xu","doi":"10.7150/ijbs.131070","DOIUrl":"10.7150/ijbs.131070","url":null,"abstract":"<p><p>Anaplastic thyroid cancer (ATC) is a lethal malignancy characterized by therapy resistance and rapid recurrence, driven in part by a population of thyroid cancer stem cells (CSCs). While the Gli1 inhibitor GANT61 targets CSC self-renewal, its efficacy is limited by compensatory activation of the pro-survival TAK1-AMPK pathway. Our present study aims to determine whether triptolide (TPL), a natural compound that inhibits TAK1 and induces reactive oxygen species (ROS), can overcome this resistance and achieve a synergistic anticancer effect when use with GANT61. Here, we report that TPL blocked GANT61-induced TAK1-AMPK activation. TPL alone effectively inhibited the proliferation of two ATC cell lines (8505C and SW1736) and achieved a synergistic anti-proliferative effect when used in combination with GANT61. Consistently, TPL alone effectively suppressed SW1736 xenograft tumor growth but, when used in combination with GANT61, prevented tumor recurrence. TPL in combination with GANT61 synergistically inhibited thyroid CSC self-renewal and induced apoptosis and pyroptosis. Mechanistically, TPL blocked GANT61-mediated activation of the TAK1-AMPK axis and synergistically induced ROS generation, which potentiated pyroptotic activity of Gasdermin D and E (GSDMD/E). This was confirmed by the evidence that TAK1 and AMPK inhibition by gene knockout or their specific inhibitors enhanced apoptotic and pyroptotic activity of GANT61, whereas ROS scavenge blocked apoptosis and pyroptosis induced by TPL and/or GANT61. Taken together, our study provides mechanistic insights into how TPL overcomes a key resistance pathway in CSC target therapy and suggests that the TPL-GANT61 combination could be a promising strategy to eradicate ATC.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 14","pages":"8008-8028"},"PeriodicalIF":11.7,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074535","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 acetyltransferases and deacetylase 6 (HDAC6) Promotes Hepatic Stellate Cell Activation and Liver Fibrosis.","authors":"Ji Hyun Lee, Ann-Yae Na, Ji Hye Kim, Tae Hyun Park, Ji Hye Yang, Joo Yong Lee, Chang Yeob Han, Sohi Kang, Il Je Cho, Sangkyu Lee, Sung Hwan Ki","doi":"10.7150/ijbs.137447","DOIUrl":"https://doi.org/10.7150/ijbs.137447","url":null,"abstract":"<p><p>Liver fibrosis results from excessive extracellular matrix (ECM) deposition following chronic hepatocyte injury. Hepatic stellate cell (HSC) activation is central to fibrogenesis; however, the regulatory mechanisms controlling this process remain unclear. Protein acetylation, regulated by histone acetyltransferases and deacetylases (HDACs), modulates gene expression and protein stability. To date, no studies have explored acetylation dynamics during HSC activation using proteomic approaches. In this study, we investigated the role of acetylation in HSC activation and liver fibrosis. Proteomic profiling of primary mouse HSCs was performed to assess global protein acetylation and the expression of HDACs and SIRTs during HSC activation. Activated HSCs exhibited reduced global protein acetylation, increased HDAC2/3/6 expression, and decreased SIRTs expression. Selective inhibition of HDAC6, but not HDAC2/3, suppressed TGF-β-induced HSC activation. TGF-β increased HDAC6 expression via Smad3-dependent transcription, and HDAC6 promoted fibrogenic gene expression through Smad activation. Proteomic screening identified acetyl-CoA acetyltransferase 1 (ACAT1) as a novel HDAC6 substrate; HDAC6 overexpression enhanced ACAT1 binding and reduced its acetylation. <i>In vivo</i>, pharmacological inhibition of HDAC6 lowered ALT and AST levels and improved histological changes in fibrotic mice. Our results suggest that selective HDAC6 inhibition may represent a promising therapeutic strategy for treating liver fibrosis.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 15","pages":"8176-8192"},"PeriodicalIF":11.7,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13685615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149244320","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":"Actin cortex formation is required for integrin clustering but not activation during leukocyte adhesion.","authors":"Doulathunnisa Ahamed Younis, Raphael Serna, Wei Liu, Beiyan Zhou, Anthony T Vella, Liang Hu, Yunfeng Chen, Ji Yu, Emanuela M Bruscia, Zhichao Fan","doi":"10.7150/ijbs.137102","DOIUrl":"https://doi.org/10.7150/ijbs.137102","url":null,"abstract":"<p><p>Leukocyte recruitment is critical for tissue homeostasis and inflammatory responses. Chemokine-induced β₂ integrin-dependent adhesion is the first and most critical step of leukocyte recruitment. Previous studies have shown that crosstalk between integrins and the actin cytoskeleton is vital for the migration of adherent leukocytes. However, whether and how the actin cytoskeleton contributes to integrin-dependent leukocyte adhesion remains poorly defined. As we recently demonstrated, a defect in integrin clustering, even in the presence of normal integrin activation, is sufficient to cause an adhesion defect in cystic fibrosis monocytes. Interestingly, these defects were accompanied by a concomitant deficiency in actin cortex formation, suggesting that actin cortex formation specifically facilitates integrin clustering rather than activation. In this study, we test this hypothesis by using the pharmacological actin polymerization inhibitor cytochalasin D (CytoD) in both human and mouse monocytes. Interestingly, we found that CytoD selectively impaired chemokine-induced actin cortex formation, yet had no impact on the total amount of polymerized F-actin. Using super-resolution microscopy, we found that inhibiting actin cortex formation directly suppressed integrin clustering but not integrin activation. Cells with inhibited actin cortex formation prevented Coronin 1A (CORO1A) binding to integrins, suggesting that the actin cortex is critical for CORO1A recruitment to integrins and thereby facilitates integrin clustering. Expanding beyond the integrin-activation-centric leukocyte adhesion paradigm, we underscore the importance of integrin clustering and identify that the actin cortex specifically regulates integrin clustering but not activation. This fundamental finding warrants investigation into selective targeting in the design of therapeutic strategies for inflammation.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 15","pages":"8158-8175"},"PeriodicalIF":11.7,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13685610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149244228","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}