The anti-ferroptotic role of FSP1: current molecular mechanism and therapeutic approach

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. A recent article by Mishima et al. in Nature demonstrated another mechanism of ferroptosis suppressor protein 1 (FSP1)-mediated ferroptosis resistance [1], motivating to summarize the anti-ferroptotic role of FSP1. Ferroptosis is a form of regulated cell death characterized by iron-dependent accumulation of harmful lipid peroxides. Glutathione peroxidase 4 (GPX4), the central regulator that contracts ferroptosis, converts lipid hydroperoxides into non-toxic lipid alcohols in concert with glutathione [2]. However, GPX4 inhibition has failed to trigger ferroptosis in several cancer cell lines, indicating the existence of an alternative mechanism of ferroptosis resistance. Using unbiased genetic screens, FSP1 has been identified as a novel ferroptosis suppressor protein and a second mainstay of ferroptosis control after GPX4 [3, 4]. FSP1 was previously called flavoprotein apoptosisinducing factor mitochondria-associated 2 (AIFM2). It was renamed FSP1 for its anti-ferroptotic role. FSP1 mainly localizes to the periphery of lipid droplets and to the plasma membrane. It also partly overlaps with the endoplasmic reticulum and Golgi. Bersuker et al. and Doll et al. independently reported that N-myristylation of FSP1 is essential for its anti-ferroptotic activity [3, 4]. Bersuker et al. demonstrated that N-myristylationdependent recruitment of FSP1 to the plasma membrane promotes resistance to ferroptosis. Once recruited, FSP1 suppresses lipid hydroperoxides by catalyzing the reduction of ubiquinone (CoQ10) to its hydroquinone form, ubiquinol (CoQ10-H2), and the consumption of NAD(P)H [3]. These findings were further validated through co-autoxidation experiments with egg phosphatidylcholine and STY-BODIPY, using a lipophilic alkoxyl radical generator. In addition, considering the ready autoxidation of CoQ10-H2, α-tocopherol could either be reproduced indirectly via CoQ10-H2 or directly in vitro by FSP1 to function as a reactive radical-trapping antioxidant [4]. Interestingly, through inhibiting CoQ biosynthesis enzyme COQ2 with 4-chlorobenzoic acid (4-CBA) or knocking out COQ2, acute reduction of cellular CoQ levels exerts a lower degree of sensitization to RSL3 than FSP1 knockout [3]. This suggests that FSP1 mediated mechanisms other than the FSP1CoQ10-NAD(P)H pathway may contribute to ferroptosis resistance. Dai et al. also found that FSP1 suppresses ferroptotic cell death and decreases the CoQ10 concentration following treatment with erastin, sorafenib, and RSL3 [5]. However, exogenous CoQ10 failed to reverse the ferroptotic cell death in FSP1 silencing cells. Strikingly, knockdown of FSP1 suppressed RSL3-induced charged multivesicular body protein 5 (CHMP5) and CHMP6 expression at the plasma membrane, and overexpression of CHMP5 rescued RSL3-, erastin-, and sorafenib-, induced cell death in both wild-type and FSP1 silencing cells. CHMP5 and CHMP6 are important subunits of the ESCRT-IIIdependent membrane repair machinery, which is associated with ferroptosis resistance through membrane budding and fission. These results indicate that ESCRTIII-dependent membrane repair is another mechanism underlying FSP1-mediated ferroptosis resistance. Open Access Molecular Biomedicine