ArticleNature communications2025
Deep Mutational Scanning of FDX1 Identifies Key Structural Determinants of Lipoylation and Cuproptosis.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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Who cites it
18 citing papers in PubMed.
- Eriocitrin Attenuates Diabetic Cardiomyopathy by Regulating Copper Homeostasis and Cuproptosis-Associated Pathways via SIRT7/YAP/ATP7A Signalling.Basic & clinical pharmacology & toxicology · 2026Article
- Iron, Copper, and Zinc Dyshomeostasis in Cardiovascular and Cerebrovascular Diseases: Redox Mechanisms, Evidence Levels, and Translational Prospects.International journal of molecular sciences · 2026Review
- Artesunate in Ferroptosis and Cuproptosis Regulation: Context-Dependent Mechanisms, Interplay, and Therapeutic Implications.International journal of molecular sciences · 2026Review
- Review
- Dihydrolipoamide dehydrogenase promotes hepatocellular carcinoma progression and modulates cuproptosis-dependent cell death.Functional & integrative genomics · 2026Article
- From copper imbalance to immunometabolic remodeling: cuproptosis-related vulnerability and therapeutic hypotheses in autoimmune diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- Review
- Harnessing Cuproptosis for Antitumor Immunity: A Review of Current Evidence and Therapeutic Strategies.Molecular carcinogenesis · 2026Review
- TCM-Derived Small Molecules Targeting Metabolic Vulnerabilities in NSCLC: Ferroptosis-Centered Mechanisms and Emerging Cuproptosis- and Disulfidptosis-Related Vulnerabilities.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Targeting programmed cell death: a novel therapeutic paradigm for cancer based on mode-of-death classification.Apoptosis : an international journal on programmed cell death · 2026Review
- Cuproptosis in Sepsis: Cell Type-Specific Mechanisms and Clinical Prospects.Drug design, development and therapy · 2026Review
- Epigenetic regulation of cuproptosis in cancer: mechanisms, microenvironment, and therapeutic implications.Frontiers in cell and developmental biology · 2026Review
- Research progress of cuproptosis, ferroptosis, apoptosis, and autophagy in knee osteoarthritis.Frontiers in cell and developmental biology · 2026Review
- Beyond apoptosis: harnessing natural products to target alternative regulated cell death for overcoming multidrug resistance in cancer.Frontiers in oncology · 2026Review
- Copper homeostasis and cuproptosis in tumor biology: mechanistic insights and clinical perspectives.Frontiers in immunology · 2026Review
- Copper-regulated cell death after spinal cord injury: evidence boundaries for non-coding RNA, epigenetics and cuproptosis.Frontiers in molecular neuroscience · 2026Review
- Roles of cuproptosis in central nervous system tumors: from molecular mechanisms to therapeutic prospects.Frontiers in cell and developmental biology · 2026Review
- Copper-Iron Cell Death Axis: Mechanistic Crosstalk, Disease Implications and an Integrated Metallo-Redox-Metabolic Framework.International journal of biological sciences · 2026Review
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
Cuproptosis is a recently described form of regulated cell death triggered by ionophore-induced copper (Cu) overload in mitochondria. It is critically dependent on ferredoxin 1 (FDX1), a mitochondrial iron-sulfur cluster containing protein that acts as an electron shuttle. FDX1 reduces ionophore-bound Cu(II) to Cu(I), thereby triggering its release, and promotes mitochondrial protein lipoylation, which is directly targeted by the released copper to drive cell death. Despite the pivotal role of FDX1 in cuproptosis, the structural determinants underlying its distinct functions remain unclear. To address this, we performed deep mutational scanning on FDX1 and find that two conserved solvent-exposed residues, D136 and D139, on alpha helix 3 are essential for both cuproptosis and lipoylation. Charge-reversal mutations at these positions abolish FDX1's ability to induce cuproptosis and support lipoylation in cells, despite retaining full enzymatic activity in vitro. Guided by structural and genomic analyses, we further identify dihydrolipoamide dehydrogenase (DLD), the E3 subunit of lipoylated complexes as an alternative FDX1 reductase both in cells and in vitro. Together, these findings establish the acidic alpha helix 3 of FDX1 as a critical interface for its upstream regulation and suggest that FDX1's roles in cuproptosis and in lipoylation are both structurally and functionally linked.
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