"RNF126 acts as an anti-ferroptotic gene by interacting with ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) and ubiquitinating FSP1 at the 4KR-2 sites"

"the deletion of RNF126 reduces the subcellular localization of FSP1 in the plasma membrane, resulting in an increase in the CoQ/CoQH2 ratio"

"The RNF126-FSP1-CoQ10 pathway plays a pivotal role in suppressing phospholipid peroxidation and ferroptosis both in vivo and in vitro"

"temsirolimus sensitized liver cancer cells to ferroptosis by directly binding to and inhibiting ferroptosis suppressor protein 1 (FSP1) enzyme"

"while temsirolimus is recognized as a potent mammalian target of rapamycin (mTOR) inhibitor, its ferroptosis-inducing effect is primarily attributed to the inhibition of FSP1 rather than mTOR activity"

"the combination of temsirolimus and RSL3 effectively suppressed liver tumor progression. This tumoricidal effect was associated with increased lipid peroxidation and induction of ferroptosis"

"The carboxy-terminal domain mediates functional dimerization of FSP1, forming a homodimer that is required for the assembly of FAD- and ubiquinone-binding pockets and for catalytic activity [lv-2023-structural-insights-abstract]. A unique feature of FSP1 structure is the ~25-degree rotation of the FAD isoalloxazine ring compared to all other known FAD-dependent oxidoreductases [lv-2023-structural-insights-abstract]."

"This 6-hydroxy-FAD was identified as both an active cofactor of FSP1 and a potent anti-ferroptotic compound in its own right, adding another layer to FSP1's ferroptosis-suppressing mechanisms [lv-2023-structural-insights-abstract]."

"FSP1 has been shown to potentiate the recruitment of ESCRT-III subunits CHMP5 and CHMP6 to the plasma membrane following ferroptosis-inducing stress. This pathway operates independently of CoQ10, suggesting that FSP1 has functions beyond its enzymatic activity."

"FSP1 expression is regulated at the transcriptional level by several pathways, most notably the KEAP1-NRF2 antioxidant response pathway. Two antioxidant response elements (AREs), which are canonical NRF2 binding motifs, have been identified in the FSP1 promoter region, and ChIP-qPCR assays confirmed increased NRF2 binding to these AREs upon KEAP1 knockout."

"Consequently, KEAP1 mutations, which are common in non-small cell lung cancer (NSCLC), lead to constitutive NRF2 activation and elevated FSP1 expression, contributing to ferroptosis and radiation resistance [koppula-2022-coq-fsp1-abstract]."

"icFSP1 promotes FSP1 phase separation and condensate formation, displacing FSP1 from membranes and thereby preventing its anti-ferroptotic function [nakamura-2023-phase-separation-abstract]."

"Beyond the plasma membrane, FSP1 also localizes to the periphery of lipid droplets (LDs) [nakamura-2023-phase-separation-abstract]. Recent work has revealed that LD-localized FSP1 plays a critical role in preventing neutral lipid peroxidation."

"Notably, iFSP1 is human-specific and does not effectively inhibit murine FSP1 due to species differences in an aromatic pocket, with F360 of human FSP1 being essential for iFSP1 binding [dasilva-2023-ifsp1-inhibition-abstract]."

"We show that icFSP1, unlike iFSP1, the first described on-target FSP1 inhibitor5, does not competitively inhibit FSP1 enzyme activity, but instead triggers subcellular relocalization of FSP1 from the membrane and FSP1 condensation before ferroptosis induction, in synergism with GPX4 inhibition"

"N-terminal myristoylation, distinct amino acid residues and intrinsically disordered, low-complexity regions in FSP1 were identified to be essential for FSP1-dependent phase separation in cells and in vitro"

"icFSP1 impairs tumour growth and induces FSP1 condensates in tumours in vivo"

"We report the crystal structures of cFSP1 (residues 12–373, hereafter named cFSP1ΔN) in its substrate-free and ubiquinone (CoQ1)-bound forms at 2.0 and 2.6 Å resolution"

"The structures reveal a FAD-binding domain and a NAD(P)H-binding domain, both of which are shared with AIF and NADH oxidoreductases4-9, and a characteristic carboxy-terminal domain as well"

"the isoalloxazine ring of the FAD in cFSP1 rotates ~ 25 degrees compared with that in all known structures of other FAD-dependent oxidoreductases"

"identify that FSP1 can catalyze the production of H2O2 and the conversion of FAD to 6-hydroxy-FAD in the presence of oxygen and NAD(P)H in vitro, and 6-hydroxy-FAD directly inhibits ferroptosis in cells"

"KEAP1 mutation or deficiency in lung cancer cells upregulates FSP1 expression through NRF2"

"the ubiquinone (CoQ)-FSP1 axis mediates ferroptosis- and radiation- resistance in KEAP1 deficient lung cancer cells"

"In this study, we identify ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) as a transcriptional target of nuclear factor erythroid 2-related factor 2 (NRF2) and reveal that the ubiquinone (CoQ)-FSP1 axis mediates ferroptosis- and radiation- resistance in KEAP1 deficient lung cancer cells"

"two antioxidant response elements (AREs) which are well-established NRF2 binding motif were found in FSP1 gene promoter regions"

"ChIP-qPCR assay was performed to verify the increased binding of NRF2 to the AREs of FSP1 upon KEAP1 knockout"

"suggesting the indispensable role of NRF2 in the regulation of FSP1 expression and ferroptosis sensitivity"

"explore the species-specific inhibition of iFSP1 on the human isoform to gain insights into its mechanism of action"

"establish a critical contribution of a species-specific aromatic architecture that is essential for target engagement"

"pose a cautionary notice for using iFSP1 in animal models, specifically murine models"