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<p>Glioblastoma stem cells (GSCs) are refractory to first-line treatment in the clinic, which includes irradiation (IR) and temozolomide (TMZ). Here we find that disrupting stress granules (SGs) sensitizes GSCs to IR/TMZ through ferroptosis. The profiling of SG proteins reveals the recruitment of iron-related proteins including ferritin. Mechanistically, G3BP1, an SG core protein, directly interacts with ferritin light chain in an IR/TMZ-induced G3BP1 methionine-333 oxidation-dependent manner. This interaction facilitates recruiting and sequestering ferritin into SGs, thereby restricting ferroptosis by limiting Fe<sup>2+</sup> content in the labile iron pool and preventing ferritinophagy. Disrupting G3BP1 and ferritin light chain binding using a screened small molecule, ciwujianoside C3, mitigates the restriction of SGs on ferroptosis, and resensitizes GSCs to IR/TMZ in both in vitro and animal models. These findings unveil a negative regulation of SGs on ferroptosis, and reveal a promising strategy to disrupt the SG–ferroptosis axis for treating glioblastomas and probably other types of cancer.</p>

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Stress granules restrain ferroptosis by sequestering ferritin

  • 期刊论文

  • 发表日期：

    2026年5月22日

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  • Zehe Ge,
  • Zihan Wang,
  • Erjie Zhao,
  • Yizhuo Guo,
  • Longxiu Zhang,
  • Fuwei Tian,
  • Mengdie Li,
  • Yunfei Ma,
  • Fangshu Ding,
  • Liuguijie He,
  • Shuhong Sun,
  • Minfeng Tong,
  • Wenxia Xu,
  • Xiefeng Wang,
  • Junxia Zhang,
  • Lingxiang Wu,
  • Yudan Zhang,
  • Lili Niu,
  • Qianghu Wang,
  • Rong Yin,
  • Xiao Li,
  • Yongping You,
  • Jeremy N. Rich,
  • Xiuxing Wang,
  • Bing Yao,
  • Zhumei Shi,
  • Zhou Yang,
  • Xin Ge,
  • Fang Liu,
  • Bo Chu,
  • Xu Qian

摘要

Glioblastoma stem cells (GSCs) are refractory to first-line treatment in the clinic, which includes irradiation (IR) and temozolomide (TMZ). Here we find that disrupting stress granules (SGs) sensitizes GSCs to IR/TMZ through ferroptosis. The profiling of SG proteins reveals the recruitment of iron-related proteins including ferritin. Mechanistically, G3BP1, an SG core protein, directly interacts with ferritin light chain in an IR/TMZ-induced G3BP1 methionine-333 oxidation-dependent manner. This interaction facilitates recruiting and sequestering ferritin into SGs, thereby restricting ferroptosis by limiting Fe2+ content in the labile iron pool and preventing ferritinophagy. Disrupting G3BP1 and ferritin light chain binding using a screened small molecule, ciwujianoside C3, mitigates the restriction of SGs on ferroptosis, and resensitizes GSCs to IR/TMZ in both in vitro and animal models. These findings unveil a negative regulation of SGs on ferroptosis, and reveal a promising strategy to disrupt the SG–ferroptosis axis for treating glioblastomas and probably other types of cancer.