The CoQ oxidoreductase FSP1 acts in parallel to GPX4 to inhibit ferroptosis

By K. Bersuker, Joseph M. Hendricks, Zhipeng Li, Leslie Magtanong, Breanna Ford, Peter H. Tang, Melissa A. Roberts, Bingqi Tong, T. J. Maimone, Roberto Zoncu and 4 more. Nature, 2019

3,124 citations recorded by the source corpus.

Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols3,4. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions2, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death5. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines6, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR–Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q10 (CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents. A synthetic lethal CRISPR–Cas9 screen identifies ferroptosis suppressor protein 1 as a key ferroptosis-resistance factor, the expression of which correlates with ferroptosis resistance in hundreds of cancer cell lines.

Subfields: Molecular Biology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/d92ecc7ad42521a6e01d998e331b90fb80804b8a

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Citations in the corpus

Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, positive): “Two groups reported that the gene product formerly known as AIFM2, and renamed FSP1, functions to regenerate the reduced form of CoQ10 through the use of nicotinamide adenine dinucleotide phosphate (NADPH), the cell’s major source of reducing power (Bersuker et al., 2019; Doll et al., 2019).”
Emerging mechanisms and disease relevance of ferroptosis (2020, background): “In addition, the newly discovered ferroptosis-inhibitory protein FSP1 provides another potential therapeutic target, considering that this protein is expressed in many cancer cells [31,32].”
Iron Metabolism in Ferroptosis (2020, background): “In addition, several GPX4-independent anti-ferroptosis pathways have recently been identified, such as the apoptosis-inducing factor mitochondria-associated 2 (AIFM2)-mediated CoQ10 production pathway (Bersuker et al., 2019; Doll et al., 2019), and the endosomal sorting complex required for transpor”
Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, background): “Subsequently, CoQ10H2 robustly halted the dissemination of lipid peroxides [62].”
Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “48 Moreover, FSP1 was identi ﬁ ed as a vitamin K reductase to generate its associated hydroquinone, which inhibits lipid peroxidation at the expense of NAD(P)H. 56 A recent study also suggested that phase separation of FSP1 plays a role in promoting ferroptosis which requires N-terminal…”