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Itaconic acid induces ferroptosis by activating ferritinophagy.
- Source :
-
Biochemical & Biophysical Research Communications . Dec2021, Vol. 583, p56-62. 7p. - Publication Year :
- 2021
-
Abstract
- 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. • Itaconic acid induces iron-dependent ferroptosis. • Itaconic acid induces ferritinophagy-dependent ferroptosis. • Itaconic acid-induced NFE2L2 activation prevents ferroptosis. • Itaconic acid suppresses tumor growth in vivo. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 0006291X
- Volume :
- 583
- Database :
- Academic Search Index
- Journal :
- Biochemical & Biophysical Research Communications
- Publication Type :
- Academic Journal
- Accession number :
- 153493285
- Full Text :
- https://doi.org/10.1016/j.bbrc.2021.10.054