Qu Chunjing, Dai Enyong, Lai Tianru, Cao Guohua, Liu Jiao, Kang Rui, Han Leng, Tang Daolin, Zhou Di
Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China.
The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
Biochem Biophys Res Commun. 2021 Oct 25;583:56-62. doi: 10.1016/j.bbrc.2021.10.054.
Itaconic acid is an unsaturated dicarbonic acid. It has a wide range of applications in the industrial production of resins and is also a mediator of immunometabolism in macrophages. Here, we show a previously unrecognized role of itaconic acid in triggering ferroptosis, a form of iron-dependent cell death driven by lipid peroxidation. We found that supraphysiological itaconic acid dose-dependently induces ferroptosis, rather than apoptosis, in human cancer cell lines. Mechanistically, we determined that itaconic acid activates NOCA4-mediated ferritinophagy, which leads to ferroptosis through ferritin degradation and subsequent iron overload and oxidative damage. In contrast, itaconic acid-induced expression and activation of NFE2L2 serves as a defense mechanism to limit ferroptosis by producing antioxidant genes. Consequently, impaired NCOA4 expression prevented, whereas a disrupted NFE2L2 pathway enhanced, sensitivity to itaconic acid-induced ferroptosis in vitro and in xenograft models. These findings establish a dynamic model of metabolite-induced ferroptotic cancer cell death, which may contribute to the development of new targeted therapies.
衣康酸是一种不饱和二碳酸。它在树脂的工业生产中有广泛应用，也是巨噬细胞免疫代谢的介质。在此，我们展示了衣康酸在触发铁死亡（一种由脂质过氧化驱动的铁依赖性细胞死亡形式）方面此前未被认识到的作用。我们发现，超生理剂量的衣康酸在人癌细胞系中剂量依赖性地诱导铁死亡，而非细胞凋亡。从机制上讲，我们确定衣康酸激活了由NCOA4介导的铁蛋白自噬，通过铁蛋白降解以及随后的铁过载和氧化损伤导致铁死亡。相反，衣康酸诱导的NFE2L2表达和激活作为一种防御机制，通过产生抗氧化基因来限制铁死亡。因此，NCOA4表达受损可预防铁死亡，而NFE2L2途径破坏则增强了体外和异种移植模型中对衣康酸诱导铁死亡的敏感性。这些发现建立了一个代谢物诱导的铁死亡癌细胞死亡的动态模型，这可能有助于开发新的靶向治疗方法。
