CIL56 is a potent and selective ferroptosis inducer. Ferroptosis is an iron-dependent form of regulated cell death (RCD).

Ferroptosis is a non-apoptotic form of regulated cell death observed in cancer cells, kidney cells and neurons.CIL56 induces iron-dependent reactive oxygen species (ROS). Antioxidants and iron chelators only suppress the lethality of low concentrations of CIL56^[1]. CIL56 triggers cell death dependent upon the rate-limiting de novo lipid synthetic enzyme ACC1.Using mass spectrometry, the metabolome of HT-1080 cells treated with CIL56 (6.5 μM)±TOFA (4 μM) is analyzed, compared to vehicle-treated controls. Among the 298 polar and nonpolar metabolites identified in this analysis, the levels of 141 metabolites are significantly altered by CIL56 treatment, with 82 metabolites significantly increased and 59 significantly decreased (FDR q<0.01). CIL56 triggers the striking TOFA-sensitive accumulation of all detectable long chain saturated and monounsaturated fatty acids and all detectable polyunsaturated fatty acids. A plausible model to account for the accumulation of both nonessential and essential fatty acids species is that CIL56 inhibits the normal breakdown of fatty acids by mitochondrial β-oxidation. CIL56 accelerates the ACC1-dependent production of malonyl-CoA, a metabolite that acts as a negative regulator of this process^[2].

• [1]. Shimada K, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol. 2016 Jul;12(7):497-503.

  [2]. Dixon SJ, et al. Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death. ACS Chem Biol. 2015 Jul 17;10(7):1604-9.