2. Academic Validation
  3. Itaconic acid induces ferroptosis by activating ferritinophagy

Itaconic acid induces ferroptosis by activating ferritinophagy

  • Biochem Biophys Res Commun. 2021 Oct 25:583:56-62. doi: 10.1016/j.bbrc.2021.10.054.
Chunjing Qu 1,  Enyong Dai 1,  Tianru Lai 1,  Guohua Cao 1,  Jiao Liu 2,  Rui Kang 3,  Leng Han 4,  Daolin Tang 5,  Di Zhou 6
Affiliations

Affiliations

  • 1 Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China.
  • 2 The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
  • 3 Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 4 Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China. Electronic address: hanleng@jlu.edu.cn.
  • 5 Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA. Electronic address: daolin.tang@utsouthwestern.edu.
  • 6 Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China. Electronic address: zhoudi2013@jlu.edu.cn.
PMID: 34735880 DOI: 10.1016/j.bbrc.2021.10.054
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.

Keywords

Autophagy; Ferroptosis; Itaconic acid; Metabolism; Transcription factor.

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