Nature cell biology · 2026
Stress granules restrain ferroptosis by sequestering ferritin.
СтатьяНазвание и аннотация: Перевод в очереди
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Ge Zehe, Wang Zihan, Zhao Erjie, Guo Yizhuo, Zhang Longxiu, Tian Fuwei, Li Mengdie, Ma Yunfei, Ding Fangshu, He Liuguijie, Sun Shuhong, Tong Minfeng, Xu Wenxia, Wang Xiefeng, Zhang Junxia, Wu Lingxiang, Zhang Yudan, Niu Lili, Wang Qianghu, Yin Rong, Li Xiao, You Yongping, Rich Jeremy N, Wang Xiuxing, Yao Bing, Shi Zhumei, Yang Zhou, Ge Xin, Liu Fang, Chu Bo, Qian Xu
Аннотация
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.