Lin Zhi, Zhong Chonglei, Shi Ming, Long Qinpeng, Jing Liang, Yu Yang, Chou Jing, Chen Miao, Lan Minhuan, Long Fei
Department of Pediatrics, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Cell Death Dis. 2025 Jun 5;16(1):436. doi: 10.1038/s41419-025-07759-x.
Ferroptosis, an iron-dependent form of programmed cell death, holds promise for cancer treatment. Circular RNAs (circRNAs), widely expressed across tumor types, modulate multiple cellular biological processes, including ferroptosis. However, the regulatory dynamics of circRNAs in gastric cancer (GC)-associated ferroptosis remain poorly understood. Here, circTFRC (circBase ID: hsa_circ_0068606), a novel circRNA, was identified as significantly upregulated in GC tissues and cell lines, with its plasma levels strongly associated with tumor size and metastatic status. Targeted suppression of circTFRC enhanced ferroptotic cell death, resulting in reduced proliferation and motility of GC cells in vitro. At the molecular level, circTFRC bound directly to SCD1 mRNAs, stabilizing and enhancing their translation via recruiting the RNA-binding protein ELAVL1. Elevated SCD1 expression mitigated ferroptosis and promoted oncogenic lipid metabolic reprogramming, thereby driving GC progression. In vivo studies further confirmed that circTFRC silencing promoted ferroptosis and inhibited tumor growth and progression. These results delineate a circTFRC-mediated axis that impairs ferroptosis vulnerability in GC cells and supports malignancy advancement. CircTFRC emerges as a biomarker with diagnostic potential and a candidate for therapeutic intervention targeting ferroptosis in GC.
铁死亡是一种铁依赖性的程序性细胞死亡形式，在癌症治疗方面具有前景。环状RNA（circRNA）广泛表达于多种肿瘤类型中，可调节包括铁死亡在内的多个细胞生物学过程。然而，circRNA在胃癌（GC）相关铁死亡中的调控动态仍知之甚少。在这里，一种新的circRNA，即circTFRC（circBase ID：hsa_circ_0068606），被鉴定为在GC组织和细胞系中显著上调，其血浆水平与肿瘤大小和转移状态密切相关。靶向抑制circTFRC可增强铁死亡细胞死亡，导致GC细胞在体外的增殖和运动能力降低。在分子水平上，circTFRC直接与SCD1 mRNA结合，通过招募RNA结合蛋白ELAVL1来稳定并增强其翻译。SCD1表达升高可减轻铁死亡并促进致癌性脂质代谢重编程，从而推动GC进展。体内研究进一步证实，circTFRC沉默可促进铁死亡并抑制肿瘤生长和进展。这些结果描绘了一个circTFRC介导的轴，该轴损害了GC细胞中铁死亡的易感性并支持恶性进展。CircTFRC成为一种具有诊断潜力的生物标志物以及针对GC中铁死亡进行治疗干预的候选物。
