Blocking the Acsl14 Enzyme Prevents Ferroptosis-Linked Cell Death

Inhibiting the enzyme Acsl4 (acyl-CoA synthetase long-chain family member 4), which is involved in fatty acid metabolism, has been postulated to be a viable therapeutic approach to preventing ferroptosis-related diseases.

Ferroptosis, a poorly understood form of programmed cell death, has been implicated in the pathological cell death found in neuronal and kidney tissues. It may also be possible to selectively trigger ferroptosis in certain cancer cells. Previously, only a few essential molecules, such as glutathione peroxidase 4 (Gpx4), have been implicated in the ferroptotic process.

Investigators at Helmholtz Zentrum München (Germany) applied two independent approaches - a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines - to generate new details as to how ferroptosis works.

They reported in the November 14, 2016, online edition of the journal Nature Chemical Biology that ACSL4 was as an essential component for ferroptosis execution. Specifically, cells in which the genes for both Gpx4 and Acsl4 proteins had been removed showed marked resistance to ferroptosis. Mechanistically, Acsl4 enriched cellular membranes with long polyunsaturated omega-6 fatty acids. Targeting Acsl4 with thiazolidinediones, a class of antidiabetic compound, prevented tissue destruction in a mouse model of ferroptosis, Moreover, Acsl4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis.

"The individual mechanisms involved in this type of cell death remain only partly understood, and our findings make an important contribution towards a better understanding of ferroptotic cell death," said senior author Dr. Marcus Conrad, head of a research group at the institute of developmental genetics at the Helmholtz Zentrum München. "Our intriguing insights that the Acsl4 enzyme plays a substantial role in the process of cell death provide novel cues for yet-unrecognized therapeutic approaches towards inhibiting ferroptosis in degenerative diseases or inducing ferroptosis in certain tumor diseases. In particular, tumors that are otherwise very difficult to treat with standard chemotherapy might be amenable for ferroptosis therapy."

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