Identification of ACSL4 as a biomarker and contributor of ferroptosis

Hua Yuan, Xuemei Li, Xiuying Zhang, Rui Kang, Daolin Tang

Research output: Contribution to journalArticle

113 Scopus citations

Abstract

Ferroptosis, a recently identified form of non-apoptotic cell death, is involved in several physiological and pathological processes. Although lipid peroxidation plays a central role in triggering ferroptosis, the essential regulator of lipid metabolism in ferroptosis remains poorly defined. Here, we show that acyl-CoA synthetase long-chain family member 4 (ACSL4) is required for ferroptotic cancer cell death. Compared with ferroptosis-sensitive cells (e.g., HepG2 and HL60), the expression of ACSL4 was remarkably downregulated in ferroptosis-resistant cells (e.g., LNCaP and K562). In contrast, the expression of other ACSLs, including ACSL1, ACSL3, ACSL5, and ACSL6, did not correlate with ferroptosis sensitivity. Moreover, knockdown of ACSL4 by specific shRNA inhibited erastin-induced ferroptosis in HepG2 and HL60 cells, whereas overexpression of ACSL4 by gene transfection restored sensitivity of LNCaP and K562 cells to erastin. Mechanically, ACSL4-mediated production of 5-hydroxyeicosatetraenoic acid (5-HETE) contributed to ferroptosis. Pharmacological inhibition of 5-HETE production by zileuton limited ACSL4 overexpression-induced ferroptosis. Collectively, these results indicate that ACSL4 is not only a sensitive monitor of ferroptosis, but also an important contributor of ferroptosis.

Original languageEnglish (US)
Pages (from-to)1338-1343
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume478
Issue number3
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Keywords

  • ACSL
  • Biomarker
  • Ferroptosis
  • Hydroxyeicosatetraenoic acid
  • Lipid metabolism

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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