title: Identification of ACSL4 as a biomarker and contributor of ferroptosis.
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.
authors: School of Nursing, Jilin University, Changchun, Jilin, 130021, China.
authors: Hua
authors: H
authors: Yuan
authors: Department of Hematology, Qingdao Municipal Hospital, Qingdao, Shandong, 261041, China.
authors: Xuemei
authors: X
authors: Li
authors: School of Nursing, Jilin University, Changchun, Jilin, 130021, China.
authors: Xiuying
authors: X
authors: Zhang
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors: Rui
authors: R
authors: Kang
authors: School of Nursing, Jilin University, Changchun, Jilin, 130021, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510150, China. Electronic address: tangd2@upmc.edu.
authors: Daolin
authors: D
authors: Tang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D003066:Coenzyme A Ligases / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D010879:Piperazines / Q000494:pharmacology; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D014408:Biomarkers, Tumor; D006893:Hydroxyeicosatetraenoic Acids; D010879:Piperazines; C477224:erastin; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
keywords: ACSL; Biomarker; Ferroptosis; Hydroxyeicosatetraenoic acid; Lipid metabolism