Itaconic acid induces ferroptosis by activating ferritinophagy

Chunjing Qu, Enyong Dai, Tianru Lai, Guohua Cao, Jiao Liu, Rui Kang, Leng Han, Daolin Tang, Di Zhou

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)56-62
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume583
DOIs
StatePublished - Dec 17 2021

Keywords

  • Autophagy
  • Ferroptosis
  • Itaconic acid
  • Metabolism
  • Transcription factor

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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