Qiu Li, Li Wenfang, Zhang Lei, Zhang Xia, Zhao Hezhao, Miyagishi Makoto, Wu Shourong, Kasim Vivi
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China.
Acta Pharm Sin B. 2025 Apr;15(4):2039-2058. doi: 10.1016/j.apsb.2025.02.013. Epub 2025 Feb 17.
Resistance to ferroptosis, a form of regulated cell death caused by disruptions in iron ion and intracellular redox homeostasis, is closely related to tumorigenesis and tumor drug resistance; therefore, targeting ferroptosis-related pathways has garnered attention as a potential antitumor therapeutic strategy. However, the molecular mechanisms underlying ferroptosis resistance in tumor cells remain unknown. Zinc-finger estrogen receptor interaction clone 6 (ZER6) consists of two isoforms with distinct N-termini, p52-ZER6 and p71-ZER6. ZER6 is upregulated in tumors and promotes tumorigenic potential; however, whether ZER6 is involved in tumor cell ferroptosis resistance remains unknown. Herein, we identified p52-ZER6 as a novel regulator of tumor cell ferroptosis resistance. p52-ZER6 promotes the transcriptional activity of , an RNA-binding protein. DAZAP1, in turn, enhances the stability of mRNA by binding to its 3'-UTR region, thereby increasing SLC7A11 expression and cellular glutathione levels. This subsequently reduces lipid peroxide accumulation and enhances tumor cell ferroptosis resistance, eventually promoting tumorigenic potential. These findings reveal a new function of p52-ZER6 in regulating mRNA stability DAZAP1, ultimately leading to ferroptosis resistance and tumorigenic potential. Additionally, we also suggest targeting p52-ZER6 as a potential strategy to promote the efficacy of ferroptosis-based antitumor therapies.
铁死亡是一种由铁离子和细胞内氧化还原稳态破坏引起的程序性细胞死亡形式，对铁死亡的抗性与肿瘤发生和肿瘤耐药性密切相关；因此，靶向铁死亡相关途径作为一种潜在的抗肿瘤治疗策略已受到关注。然而，肿瘤细胞中铁死亡抗性的分子机制仍然未知。锌指雌激素受体相互作用克隆6（ZER6）由两种具有不同N端的异构体p52-ZER6和p71-ZER6组成。ZER6在肿瘤中上调并促进肿瘤发生潜能；然而，ZER6是否参与肿瘤细胞对铁死亡的抗性仍不清楚。在此，我们确定p52-ZER6是肿瘤细胞铁死亡抗性的一种新型调节因子。p52-ZER6促进RNA结合蛋白DAZAP1的转录活性。反过来，DAZAP1通过与其3'-UTR区域结合来增强mRNA的稳定性，从而增加SLC7A11表达和细胞内谷胱甘肽水平。这随后减少了脂质过氧化物的积累并增强了肿瘤细胞对铁死亡的抗性，最终促进了肿瘤发生潜能。这些发现揭示了p52-ZER6在调节DAZAP1 mRNA稳定性方面的新功能，最终导致铁死亡抗性和肿瘤发生潜能。此外，我们还建议将靶向p52-ZER6作为一种潜在策略来提高基于铁死亡的抗肿瘤治疗的疗效。
