Wu Chaorui, Yan Yu, Chen Qichen, Lian Zhiying, He Jiayong, Ling Ruoyu, Lei Xuetao, Peng Yanmei, Zheng Boyang, Yang Qingbin, Ye Gengtai, Ma Wenhui, Li Guoxin
Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Department of Immunology, Shenzhen Majory Biotechnology Co. Ltd., Shenzhen, China.
Commun Biol. 2025 Aug 13;8(1):1208. doi: 10.1038/s42003-025-08584-w.
Stress granules (SGs), which are phase-separating organelles that serve as protective cellular mechanisms in response to various harmful stimuli, have an unclear role in oxaliplatin resistance. Here, we establish a causal link between SG formation and oxaliplatin resistance in GC. Notably, we identify a key SG nucleator, namely, ubiquitin-associated protein 2-like (UBAP2L), as a previously unrecognized critical factor in mediating oxaliplatin resistance. UBAP2L-nucleated SG-mediated inhibition of apoptosis is associated with the recruitment of receptor of activated protein C kinase 1 (RACK1), a known promoter of apoptosis, to these entities. Transcriptional upregulation of UBAP2L is enhanced by oxaliplatin-induced phosphorylation and activation of heat shock factor protein 1 (HSF1) via AKT. Inhibiting either SG or HSF1 significantly overcomes oxaliplatin resistance in vivo. These findings demonstrate that UBAP2L-nucleated SGs play a vital role in mediating oxaliplatin resistance, with elevated SG levels emerging as a promising therapeutic target for overcoming this resistance.
应激颗粒（SGs）是一种相分离细胞器，作为细胞对各种有害刺激的保护机制，其在奥沙利铂耐药中的作用尚不清楚。在此，我们建立了SG形成与胃癌中奥沙利铂耐药之间的因果联系。值得注意的是，我们鉴定出一个关键的SG成核因子，即泛素相关蛋白2样（UBAP2L），它是介导奥沙利铂耐药的一个先前未被认识的关键因素。UBAP2L成核的SG介导的细胞凋亡抑制与凋亡已知促进因子——活化蛋白C激酶1受体（RACK1）募集到这些实体有关。奥沙利铂通过AKT诱导热休克因子蛋白1（HSF1）磷酸化和激活，从而增强UBAP2L的转录上调。在体内抑制SG或HSF1可显著克服奥沙利铂耐药。这些发现表明，UBAP2L成核的SG在介导奥沙利铂耐药中起重要作用，SG水平升高成为克服这种耐药的一个有前景的治疗靶点。
