TY - JOUR
T1 - Itaconic acid induces ferroptosis by activating ferritinophagy
AU - Qu, Chunjing
AU - Dai, Enyong
AU - Lai, Tianru
AU - Cao, Guohua
AU - Liu, Jiao
AU - Kang, Rui
AU - Han, Leng
AU - Tang, Daolin
AU - Zhou, Di
N1 - Funding Information:
We thank Dave Primm (Department of Surgery, University of Texas Southwestern Medical Center) for his critical reading of the manuscript. This work is supported by the Natural Science Foundation of Jilin Provience of China ( 20210101331JC ).
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/12/17
Y1 - 2021/12/17
N2 - 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.
AB - 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.
KW - Autophagy
KW - Ferroptosis
KW - Itaconic acid
KW - Metabolism
KW - Transcription factor
UR - http://www.scopus.com/inward/record.url?scp=85117884175&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85117884175&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2021.10.054
DO - 10.1016/j.bbrc.2021.10.054
M3 - Article
C2 - 34735880
AN - SCOPUS:85117884175
SN - 0006-291X
VL - 583
SP - 56
EP - 62
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
ER -