ArticleProceedings of the National Academy of Sciences of the United States of America2025
Cocrystal structure reveals the mechanism of FSP1 inhibition by FSEN1.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- AI-enhanced adaptive virtual screening of large libraries for ligand discovery.Nature biotechnology · 2026Article
- CoQExperimental & molecular medicine · 2026Review
- Metabolic rewiring driven by phosphoglycolate phosphatase deletion inhibits ferroptosis.Science advances · 2026Article
- AI-Enhanced Adaptive Virtual Screening Platform Enabling Exploration of 69 Billion Molecules Discovers Structurally Validated FSP1 Inhibitors.bioRxiv : the preprint server for biology · 2026Article
- Lipids grease the chain of cancer progression.Trends in cancer · 2026Review
- Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.Nature structural & molecular biology · 2026Article
- Ferroptosis Suppressor Protein 1 (FSP1)-CoQ10-NADPH-Axis Is Responsible for Erastin Resistance in MCF-7 Breast Cancer Cells.Antioxidants (Basel, Switzerland) · 2026Article
- Targeting ferroptosis in lung cancer: pharmacological regulation, nanomedicine-based delivery, and AI-enabled translational strategies.American journal of cancer research · 2026Review
- Article
- Ferroptosis in cancer: metabolism, mechanisms and therapeutic prospects.Molecular cancer · 2025Review
- Prospects for ferroptosis therapies in cancer.Nature cancer · 2025Review
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
FSP1 is an FAD-dependent oxidoreductase that uses NAD(P)H to regenerate the reduced forms of lipophilic quinone antioxidants, such as coenzyme Q10 and vitamin K. These quinone antioxidants function as radical scavenging agents that prevent the propagation of lipid peroxidation and the induction of ferroptosis. Although several small-molecule inhibitors of FSP1 have been developed and found to sensitize cancer cells to ferroptosis, our understanding of their molecular mechanisms remains limited and no structures of FSP1 in complex with its inhibitors have been solved. Here, we solve the cocrystal structure of FSP1 in complex with the FSP1 inhibitor FSEN1, revealing that FSEN1 binds within the FSP1 substrate-binding pocket. FSEN1 makes key interactions with a critical phenylalanine, which is absent in mouse FSP1, providing an explanation for the selectivity of FSEN1 for human FSP1. These conclusions are supported by mutagenesis of FSP1 and biochemical and cellular assays of FSP1 function. Our findings provide the first cocrystal structure of FSP1 in complex with an inhibitor, enhancing our understanding of the mechanism of FSP1 inhibition and enabling future rational medicinal chemistry efforts to advance FSP1 inhibitors as therapeutics.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.