Xu Yangwei, Qian Xuexia, Cai Guixing, Lin Zhihao, Huang Weiye, Wang Chuangyuan, Wu Hongmei, Zhang Yiqiong, Sun Jingbo, Zhang Qingling
Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China.
Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China.
iScience. 2025 Feb 7;28(3):111964. doi: 10.1016/j.isci.2025.111964. eCollection 2025 Mar 21.
Gastric cancer (GC) is one of the most prevalent and lethal cancers worldwide. Ferroptosis is a form of iron-dependent regulated cell death emerging as a promising strategy for cancer therapy, whereas the regulation mechanism remains unclear. WTX has been recognized as a potential tumor suppressor, but attempts at targeted therapy have not achieved substantial progress. Further research into the structure, function, and mechanisms is urgently needed. Herein, we identified a long isoform of WTX (WTX-L) as a potent ferroptosis effector in GC. Mechanistically, WTX-L competitively interacts with β-arrestin2, disrupting its direct binding to IκBα and subsequently activating the NF-κB/LCN2 pathway. LCN2 further triggers ferroptosis by significantly increasing the labile Fe pool and promoting excessive lipid peroxidation. Blockade of the WTX-L/β-arrestin2/NF-κB/LCN2 axis significantly diminished the activity of ferroptosis inducers (erastin and RSL3) . Collectively, these findings reveal that targeting the ferroptosis vulnerabilities through WTX-L may represent a promising strategy for GC.
胃癌（GC）是全球最常见且致命的癌症之一。铁死亡是一种铁依赖性的程序性细胞死亡形式，正成为一种有前景的癌症治疗策略，但其调控机制仍不清楚。WTX已被认为是一种潜在的肿瘤抑制因子，但靶向治疗的尝试尚未取得实质性进展。迫切需要对其结构、功能和机制进行进一步研究。在此，我们鉴定出一种长异构体WTX（WTX-L）是胃癌中一种有效的铁死亡效应因子。机制上，WTX-L与β-抑制蛋白2竞争性相互作用，破坏其与IκBα的直接结合，随后激活NF-κB/LCN2通路。LCN2通过显著增加不稳定铁池和促进过度脂质过氧化进一步触发铁死亡。阻断WTX-L/β-抑制蛋白2/NF-κB/LCN2轴可显著降低铁死亡诱导剂（埃拉斯汀和RSL3）的活性。总之，这些发现表明，通过WTX-L靶向铁死亡易感性可能是一种有前景的胃癌治疗策略。
