An important factor correlated with poor survival in glioblastoma (GBM) is the aberrant and persistent activation of STAT3, a critical transcription factor that regulates multiple genes with key roles in cell survival, proliferation, resistance to chemotherapy, and stem cell maintenance. The Interleukin-6 (IL6)-STAT3 signaling axis has been studied extensively in inflammation and cancer. However, it is not completely understood how high levels of activated STAT3 are sustained in tumors. Previously, we identified a novel mechanism of biphasic activation of STAT3 in response to gp130-linked cytokines, including IL6, in which activation of STAT3 is prolonged by circumventing the negative regulatory mechanisms induced by its initial activationTo target prolonged STAT3 activation, we used the small molecule inhibitor bazedoxifene (BZA), which blocks formation of the IL6 receptor-gp130 complex. Glioma stem-like cells (GSCs) are more tumorigenic and more resistant to therapy. STAT3 is a key driver of the expression of stem cell transcription factors, making it a therapeutically important target in GBM. We show that treating GSCs with BZA decreases their self-renewal capacity and the expression of GSC markers in vitro. Additionally, BZA crosses the blood-brain barrier and confers a survival advantage in an orthotopic syngeneic mouse model of GBM. Although IL6-STAT3 signaling is important for GSC survival, a therapeutic agent that inhibits this pathway without toxicity has yet to be identified. Our findings reveal a mechanism of sustained STAT3 signaling in GBM and reveal its role in GSC maintenance, and we identify BZA as a novel candidate for treating GBM.

与胶质母细胞瘤 (GBM) 存活率差相关的一个重要因素是 STAT3 的异常和持续激活，STAT3 是一种关键转录因子，可调节在细胞存活、增殖、化疗耐药和干细胞维持中起关键作用的多个基因。白细胞介素 6 (IL6)-STAT3 信号轴已在炎症和癌症中得到广泛研究。然而，尚不完全了解如何在肿瘤中维持高水平的活化 STAT3。以前，我们确定了一种新的 STAT3 响应 gp130 相关细胞因子（包括 IL6）的双相激活机制，其中通过规避由其初始激活诱导的负调节机制来延长 STAT3 的激活为了靶向延长的 STAT3 激活，我们使用了小分子抑制剂巴多昔芬（BZA），阻断IL6受体-gp130复合物的形成。胶质瘤干细胞样细胞 (GSCs) 更具致瘤性并且对治疗更具抵抗力。STAT3 是干细胞转录因子表达的关键驱动因子，使其成为 GBM 治疗中的重要靶点。我们表明，用 BZA 处理 GSC 会降低其自我更新能力和 GSC 标志物的表达体外。此外，BZA 穿过血脑屏障并在 GBM 的原位同基因小鼠模型中赋予生存优势。尽管 IL6-STAT3 信号传导对 GSC 存活很重要，但尚未确定一种无毒性抑制该途径的治疗剂。我们的研究结果揭示了 GBM 中持续 STAT3 信号传导的机制，并揭示了其在 GSC 维持中的作用，我们将 BZA 确定为治疗 GBM 的新候选药物。