Targeting the ANXA8-SP1-PPA1 Axis to Modulate TCA Cycle and Matrix Deposition in Diffuse-Type Gastric Cancer.

IF 10.7 1区 综合性期刊 Q1 Multidisciplinary
Research Pub Date : 2025-08-25 eCollection Date: 2025-01-01 DOI:10.34133/research.0838
Yuxia Wu, Xiangyan Jiang, Huiguo Qing, Yansong Hou, Yong Ma, Tao Wang, Keshen Wang, Long Qin, Weiwen Cai, Zongrui Xing, Bin Zhao, Qichen He, Wenbo Liu, Tian Wang, Haonan Sun, Xingshuo Zhao, Zuoyi Jiao, Zeyuan Yu
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引用次数: 0

Abstract

Diffuse-type gastric cancer (DGC) is an aggressive tumor type characterized by a dense extracellular matrix (ECM). Metabolic reprogramming, a key oncogenic factor driving tumor progression, is closely linked to ECM deposition, although the regulatory mechanisms remain poorly understood. In this study, we integrated single-cell sequencing, proteomics, metabolomics, and large-scale clinical data to identify the metabolic signature of DGC. We found that the tricarboxylic acid (TCA) cycle is suppressed in DGC, which correlates with the formation of a dense ECM. Annexin A8 (ANXA8) was identified as a critical regulator that inhibits the TCA cycle in DGC and is positively associated with matrix formation. Mechanistically, ANXA8 interacts with SP1 to promote the transcription of pyrophosphatase 1, thereby suppressing the TCA cycle, activating cancer-associated fibroblasts, and facilitating aberrant ECM deposition. Deletion of ANXA8 suppresses malignant phenotypes and shows synergistic effects with the chemotherapeutic agent 5-fluorouracil (5-FU). Large-scale clinical data further confirmed the correlation between ANXA8 expression and both gastric cancer progression and 5-FU therapeutic efficacy. High-throughput organoid screening identified UNC2025 as a selective ANXA8 inhibitor. Targeting ANXA8 with UNC2025 restores TCA cycle activity and inhibits ECM deposition in DGC, enhancing the therapeutic effects of 5-FU in patient-derived xenografts and organoids. Furthermore, a polyphenol-based UNC2025 nanodelivery system improved the efficacy of this combination therapy. In summary, this study elucidates how ANXA8-mediated suppression of the TCA cycle promotes dense ECM formation and malignant progression in DGC, highlighting the therapeutic potential of targeting ANXA8 in DGC treatment.

靶向ANXA8-SP1-PPA1轴调控弥漫性胃癌TCA循环和基质沉积
弥漫性胃癌(DGC)是一种侵袭性肿瘤类型,其特征是细胞外基质(ECM)致密。代谢重编程是驱动肿瘤进展的关键致癌因子,与ECM沉积密切相关,尽管其调控机制尚不清楚。在这项研究中,我们整合了单细胞测序、蛋白质组学、代谢组学和大规模临床数据来鉴定DGC的代谢特征。我们发现三羧酸(TCA)循环在DGC中被抑制,这与致密ECM的形成有关。Annexin A8 (ANXA8)被认为是抑制DGC中TCA循环的关键调节因子,并与基质形成呈正相关。机制上,ANXA8与SP1相互作用,促进焦磷酸酶1的转录,从而抑制TCA循环,激活癌症相关成纤维细胞,促进异常ECM沉积。缺失ANXA8可抑制恶性表型,并与化疗药物5-氟尿嘧啶(5-FU)表现出协同作用。大规模临床资料进一步证实了ANXA8表达与胃癌进展及5-FU治疗效果的相关性。高通量类器官筛选确定UNC2025为选择性ANXA8抑制剂。UNC2025靶向ANXA8可恢复TCA循环活性,抑制DGC中的ECM沉积,增强5-FU在患者来源的异种移植物和类器官中的治疗效果。此外,基于多酚的UNC2025纳米递送系统提高了这种联合治疗的疗效。总之,本研究阐明了ANXA8介导的TCA周期抑制如何促进DGC中致密ECM的形成和恶性进展,突出了靶向ANXA8在DGC治疗中的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Research
Research Multidisciplinary-Multidisciplinary
CiteScore
13.40
自引率
3.60%
发文量
0
审稿时长
14 weeks
期刊介绍: Research serves as a global platform for academic exchange, collaboration, and technological advancements. This journal welcomes high-quality research contributions from any domain, with open arms to authors from around the globe. Comprising fundamental research in the life and physical sciences, Research also highlights significant findings and issues in engineering and applied science. The journal proudly features original research articles, reviews, perspectives, and editorials, fostering a diverse and dynamic scholarly environment.
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