NINJ1 was initially recognized for its role in nerve regeneration and cellular adhesion. Subsequent studies have uncovered its participation in cancer progression, where NINJ1 regulates critical steps in tumor metastasis, such as cell migration and invasion. More recently, NINJ1 has emerged as a multifunctional protein mediating plasma membrane rupture (PMR) in several lytic cell death processes, including apoptosis, necroptosis, and pyroptosis. However, its role in ferroptosis—an iron-dependent form of lytic cell death characterized by lipid peroxidation—remained unclear until 2024. Ferroptosis is a tumor suppression mechanism that may be particularly relevant to detached and metastatic cancer cells. This review explores the role of NINJ1 in tumor invasion and metastasis, focusing on its regulation of ferroptosis via a non-canonical mechanism distinct from other cell deaths. We discuss the process of ferroptosis and its implications for cancer invasion and metastasis. Furthermore, we review recent studies highlighting the diverse roles of NINJ1 in ferroptosis regulation, including its canonical function in PMR and its non-canonical function of modulating intracellular levels of glutathione (GSH) and coenzyme A (CoA) via interaction with xCT anti-porter. Given that ferroptosis has been associated with tumor suppression, metastasis, the elimination of treatment-resistant cancer cells, and tumor dormancy, NINJ1′s modulation of ferroptosis presents a promising therapeutic target for inhibiting metastasis. Understanding the dual role of NINJ1 in promoting or restraining ferroptosis depending on cellular context could open avenues for novel anti-cancer strategies to enhance ferroptotic vulnerability in metastatic tumors.
NINJ1最初因其在神经再生和细胞黏附中的作用而被发现。随后的研究揭示了它在癌症进展中的参与，NINJ1调控肿瘤转移的关键步骤，如细胞迁移和侵袭。最近，NINJ1作为一种多功能蛋白，在多种裂解性细胞死亡过程（包括凋亡、坏死性凋亡和焦亡）中介导质膜破裂（PMR）。然而，直到2024年，其在铁死亡（一种以脂质过氧化为特征的铁依赖性裂解性细胞死亡）中的作用仍不明确。铁死亡是一种肿瘤抑制机制，可能特别与脱离和转移的癌细胞相关。本综述探讨了NINJ1在肿瘤侵袭和转移中的作用，重点关注其通过不同于其他细胞死亡的非经典机制调控铁死亡。我们讨论了铁死亡的过程及其对癌症侵袭和转移的影响。此外，我们回顾了近期研究，这些研究强调了NINJ1在铁死亡调控中的多种作用，包括其在PMR中的经典功能，以及通过与xCT反向转运体相互作用调节细胞内谷胱甘肽（GSH）和辅酶A（CoA）水平的非经典功能。鉴于铁死亡与肿瘤抑制、转移、清除耐药癌细胞以及肿瘤休眠相关，NINJ1对铁死亡的调控为抑制转移提供了一个有前景的治疗靶点。理解NINJ1根据细胞环境促进或抑制铁死亡的双重作用，可能为开发新型抗癌策略以增强转移性肿瘤的铁死亡脆弱性开辟新途径。
NINJ1 in Cell Death and Ferroptosis: Implications for Tumor Invasion and Metastasis
肿瘤(癌症)患者之家