理由：神经胶质瘤干细胞（GSC）已成为肿瘤恶性肿瘤的关键驱动因素，并受到各种微环境因素（包括免疫分子和缺氧）的维持。在我们之前的研究中，我们阐明了转化生长因子β诱导蛋白（TGFBI）（一种由M2样肿瘤相关巨噬细胞分泌的蛋白质）在常氧条件下促进胶质母细胞瘤（GBM）恶性行为中的重要作用。基于这些发现，本研究的目的是全面探讨缺氧条件下 GSCs 中自分泌 TGFBI 的关键作用和潜在机制。方法：我们量化了神经胶质瘤标本和数据集中的 TGFBI 表达。采用体外和体内实验研究 TGFBI 对缺氧条件下 GSC 维持自我更新和肿瘤发生的影响。进行 RNA-seq 和 LC-MS/MS 来探索 TGFBI 信号传导机制。结果：TGFBI在低氧条件下优先在GSC中表达。靶向 TGFBI 会损害 GSC 的自我更新和肿瘤发生。从机制上讲，TGFBI 在 GSC 中被 HIF1α 上调，并通过防止 EphA2 蛋白降解来稳定 EphA2 蛋白，从而主要激活 GSC 中的 AKT-c-MYC 信号通路。结论：TGFBI在缺氧微环境中维持GSCs的干细胞特性中发挥着至关重要的作用。靶向 TGFBI/EphA2 轴已成为 GBM 治疗的一种有前途且创新的策略，有可能改善患者的临床结果。© 作者。

Rationale: Glioma stem cells (GSCs) have emerged as pivotal drivers of tumor malignancy, sustained by various microenvironmental factors, including immune molecules and hypoxia. In our previous study, we elucidated the significant role of transforming growth factor beta-induced protein (TGFBI), a protein secreted by M2-like tumor-associated macrophages, in promoting the malignant behavior of glioblastoma (GBM) under normoxic conditions. Building upon these findings, the objective of this study was to comprehensively explore the crucial role and underlying mechanisms of autocrine TGFBI in GSCs under hypoxic conditions. Methods: We quantified TGFBI expression in glioma specimens and datasets. In vitro and in vivo assays were employed to investigate the effects of TGFBI on sustaining self-renewal and tumorigenesis of GSCs under hypoxia. RNA-seq and LC-MS/MS were conducted to explore TGFBI signaling mechanisms. Results: TGFBI is preferentially expressed in GSCs under hypoxic conditions. Targeting TGFBI impair GSCs self-renewal and tumorigenesis. Mechanistically, TGFBI was upregulated by HIF1α in GSCs and predominantly activates the AKT-c-MYC signaling pathway in GSCs by stabilizing the EphA2 protein through preventing its degradation. Conclusion: TGFBI plays a crucial role in maintaining the stem cell properties of GSCs in the hypoxic microenvironment. Targeting the TGFBI/EphA2 axis emerges as a promising and innovative strategy for GBM treatment, with the potential to improve the clinical outcomes of patients.© The author(s).