Although cell-cycle arrest, senescence, and apoptosis are well accepted as the classic barriers in tumorigenesis, recent studies indicate that metabolic regulation is equally important as a major checkpoint in cancer development. It is well accepted that ferroptosis, an iron-dependent programmed cell death, acts as a new type of tumor suppression mechanism tightly linked with numerous metabolic pathways. SLC7A11 is a transmembrane cystine/glutamate transporter protein that plays a vital role in controlling ferroptosis . The levels of SLC7A11 are dynamically regulated by various types of stresses, such as oxidative stress, nutrient deprivation, endoplasmic reticulum stress, radiation, oncogenic stress, DNA damage, and immune stress. SLC7A11 can be transcriptionally regulated by both activators such as ATF4, NRF2, and ETS1, and repressors including BACH1, p53, ATF3, and STAT1 during stress responses. Moreover, SLC7A11 activity and its protein stability and cellular localization are also modulated upon stress. Patients' data show that SLC7A11 is overexpressed in various types of human cancers, and higher levels of SLC7A11 predict poorer overall survival. Growing evidence also suggests that targeting SLC7A11 is a promising approach in cancer therapy by effectively inhibiting tumor proliferation, invasion, and metastasis, as well as counteracting cancer stem cells and overcoming chemoresistance. This review highlights the regulation of SLC7A11 as an unconventional checkpoint in tumorigenesis through modulating ferroptotic responses under various types of stress.

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通过铁死亡调节 SLC7A11 作为肿瘤发生中的非常规检查点

尽管细胞周期停滞、衰老和凋亡被广泛认为是肿瘤发生的经典障碍，但最近的研究表明，代谢调节作为癌症发展中的主要检查点同样重要。人们普遍认为，铁死亡是一种铁依赖性程序性细胞死亡，是一种与多种代谢途径密切相关的新型肿瘤抑制机制。SLC7A11 是一种跨膜胱氨酸/谷氨酸转运蛋白，在控制铁死亡中发挥着至关重要的作用。SLC7A11的水平受到各种类型的应激的动态调节，例如氧化应激、营养缺乏、内质网应激、辐射、致癌应激、DNA损伤和免疫应激。在应激反应过程中，SLC7A11 可以受到 ATF4、NRF2 和 ETS1 等激活因子以及 BACH1、p53、ATF3 和 STAT1 等抑制因子的转录调节。此外，SLC7A11 活性及其蛋白质稳定性和细胞定位也会受到应激的调节。患者数据显示，SLC7A11 在各种类型的人类癌症中过度表达，SLC7A11 水平较高预示总体生存期较差。越来越多的证据还表明，靶向SLC7A11是一种有前途的癌症治疗方法，可以有效抑制肿瘤增殖、侵袭和转移，以及对抗癌症干细胞和克服化疗耐药性。这篇综述强调了 SLC7A11 通过调节各种应激下的铁死亡反应作为肿瘤发生中的非常规检查点的调节。