Itaconic acid induces ferroptosis by activating ferritinophagy

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.