FAF1 blocks ferroptosis by inhibiting peroxidation of polyunsaturated fatty acids

Abstract

Significance The current study reveals the functions of FAF1 in protecting cells from ferroptosis, a novel cell death pathway triggered by PUFA peroxidation. In the absence of FAF1, cultured cells and mice are extremely sensitive to ferroptosis when exposed to physiological levels of PUFAs. Mechanistically, FAF1 sequesters PUFAs into the hydrophobic core of a global structure that limits their access to positively charged Fe 2+ , which catalyzes the peroxidation reaction. These observations suggest that FAF1-mediated protection of PUFA peroxidation plays a critical role in preventing initiation of ferroptosis.

New anti-cancer explorations based on metal ions

“…Excessive oxidation of phospholipids in polyunsaturated fatty acids (PUFAs) also contributes to cell ferroptosis [ 34 ]. PUFAs are an essential component of the phospholipid bilayer of the cell membrane and play an indispensable role in maintaining cell membrane fluidity [ 35 ].…”

A protein‐lipid complex that detoxifies free fatty acids

“…[10] In the presence of unsaturated FAs, assembly of the FAF1-FFA complex not only enables cell proliferation by stabilization of β-catenin [10] but also prevents PUFA peroxidation to protect cells from ferroptosis. [5] Cancer genomic studies have revealed that FAF1 is frequently inactivated in glioblastoma and hereditary colorectal cancer, presumably because of their growth advantage through stabilization of β-catenin. [27,28] It will be interesting to determine whether these cancers are vulnerable to PUFA-induced ferroptosis.…”

“…However, direct visualization of the FAF1‐FFA complex in cells remains challenging as this membraneless organelle is destroyed by conventional cell fixation and permeabilization procedures for fluorescent microscopy and EM analysis that are optimized to preserve structures surrounded by membranes. [ 5 ]…”

“…A recent study demonstrated that Fas associated factor 1 (FAF1), a cytosolic protein interacting with unsaturated FFAs, [ 12 ] is crucial to detoxify free PUFAs by sequestrating them into a protein‐lipid complex. [ 5 ] This sequestration limits access of PUFAs to Fe 2+ , thereby protecting cells from ferroptosis. [ 5 ] The observations that free PUFAs in cytosol are not randomly diffused but rather sequestered into a membraneless complex shall open new directions to study FFAs in cells.…”

“…[ 5 ] This sequestration limits access of PUFAs to Fe 2+ , thereby protecting cells from ferroptosis. [ 5 ] The observations that free PUFAs in cytosol are not randomly diffused but rather sequestered into a membraneless complex shall open new directions to study FFAs in cells.…”