TY  - JOUR
AB  - In 2012, a study revealed a unique form of cell death, termed ferroptosis, that is dependent on iron and unregulated lipid peroxidation. We revisit how this paper changed the trajectory of ferroptosis research from its origins to its current state.
AU  - Conrad, M.
AU  - Wahida, A.
C1  - 72894
C2  - 56801
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 18-19
TI  - The many paths ascending to ferroptosis.
JO  - Nat. Chem. Biol.
VL  - 21
IS  - 1
PB  - Nature Portfolio
PY  - 2025
SN  - 1552-4450
ER  - 

TY  - JOUR
AB  - Diabetes is characterized by variable loss of insulin-producing beta cells, and new regenerative approaches to increasing the functional beta cell mass of patients hold promise for reversing disease progression. In this Review, we summarize recent chemical biology breakthroughs advancing our knowledge of beta cell regeneration. We present current chemical-based tools, sensors and mechanistic insights into pathways that can be targeted to enhance beta cell regeneration in model organisms. We group the pathways according to the cellular processes they affect, that is, proliferation, conversion of other mature cell types to beta cells and beta cell differentiation from progenitor-like populations. We also suggest assays for assessing the functionality of the regenerated beta cells. Although regeneration processes differ between animal models, such as zebrafish, mice and pigs, regenerative mechanisms identified in any one animal model may be translatable to humans. Overall, chemical biology-based approaches in beta cell regeneration give hope that specific molecular pathways can be targeted to enhance beta cell regeneration.
AU  - Karampelias, C.
AU  - Liu, K.C.*
AU  - Tengholm, A.*
AU  - Andersson, O.*
C1  - 73230
C2  - 56959
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Mechanistic insights and approaches for beta cell regeneration.
JO  - Nat. Chem. Biol.
PB  - Nature Portfolio
PY  - 2025
SN  - 1552-4450
ER  - 

TY  - JOUR
AB  - Half a century after its discovery, platelet-activating factor (PAF) is now recognized as a ferroptosis-activating phospholipid that contributes to tubule cell damage and nephron loss in acute kidney injury.
AU  - Zheng, J.
AU  - Proneth, B.
C1  - 69954
C2  - 55336
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Chains of death.
JO  - Nat. Chem. Biol.
PB  - Nature Portfolio
PY  - 2024
SN  - 1552-4450
ER  - 

TY  - JOUR
AB  - Glutathione peroxidase 4 (GPX4), as the only enzyme in mammals capable of reducing esterified phospholipid hydroperoxides within a cellular context, protects cells from ferroptosis. We identified a homozygous point mutation in the GPX4 gene, resulting in an R152H coding mutation, in three patients with Sedaghatian-type spondylometaphyseal dysplasia. Using structure-based analyses and cell models, including patient fibroblasts, of this variant, we found that the missense variant destabilized a critical loop, which disrupted the active site and caused a substantial loss of enzymatic function. We also found that the R152H variant of GPX4 is less susceptible to degradation, revealing the degradation mechanism of the GPX4 protein. Proof-of-concept therapeutic treatments, which overcome the impaired R152H GPX4 activity, including selenium supplementation, selective antioxidants and a deuterated polyunsaturated fatty acid were identified. In addition to revealing a general approach to investigating rare genetic diseases, we demonstrate the biochemical foundations of therapeutic strategies targeting GPX4.
AU  - Liu, H.*
AU  - Forouhar, F.*
AU  - Seibt, T.*
AU  - Saneto, R.*
AU  - Wigby, K.*
AU  - Friedman, J.*
AU  - Xia, X.*
AU  - Shchepinov, M.S.*
AU  - Ramesh, S.K.*
AU  - Conrad, M.
AU  - Stockwell, B.R.*
C1  - 63896
C2  - 51634
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 91-100
TI  - Characterization of a patient-derived variant of GPX4 for precision therapy.
JO  - Nat. Chem. Biol.
VL  - 18
IS  - 1
PB  - Nature Portfolio
PY  - 2022
SN  - 1552-4450
ER  - 

TY  - JOUR
AB  - Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes and biochemical properties. Here, we report an active humanized cone snail venom insulin with an elongated A chain and a truncated B chain, and use cryo-electron microscopy (cryo-EM) and protein engineering to elucidate its interactions with the human insulin receptor (IR) ectodomain. We reveal how an extended A chain can compensate for deletion of B-chain residues, which are essential for activity of human insulin but also compromise therapeutic utility by delaying dissolution from the site of subcutaneous injection. This finding suggests approaches to developing improved therapeutic insulins. Curiously, the receptor displays a continuum of conformations from the symmetric state to a highly asymmetric low-abundance structure that displays coordination of a single humanized venom insulin using elements from both of the previously characterized site 1 and site 2 interactions. [Figure not available: see fulltext.]
AU  - Xiong, X.*
AU  - Blakely, A.*
AU  - Kim, J.H.*
AU  - Menting, J.G.*
AU  - Schäfer, I.B.*
AU  - Schubert, H.L.*
AU  - Agrawal, R.*
AU  - Gutmann, T.
AU  - Delaine, C.*
AU  - Zhang, Y.W.*
AU  - Olay Artik, G.
AU  - Merriman, A.*
AU  - Eckert, D.*
AU  - Lawrence, M.C.*
AU  - Coskun, Ü.
AU  - Fisher, S.J.*
AU  - Forbes, B.E.*
AU  - Safavi-Hemami, H.*
AU  - Hill, C.P.*
AU  - Chou, D.H.C.*
C1  - 64603
C2  - 51940
SP  - 511-519
TI  - Symmetric and asymmetric receptor conformation continuum induced by a new insulin.
JO  - Nat. Chem. Biol.
VL  - 18
IS  - 5
PY  - 2022
SN  - 1552-4450
ER  - 

TY  - JOUR
AB  - Ferroptosis is a regulated form of non-apoptotic cell death implicated in pathological settings. To be exploited clinically, ferroptosis requires reagents that unequivocally detect ferroptosis in human and animal tissues. Such tools may enable development of ferroptosis-based medicines for diverse diseases.
AU  - Hadian, K.
AU  - Stockwell, B.R.*
C1  - 63348
C2  - 51301
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1113-1116
TI  - A roadmap to creating ferroptosis-based medicines.
JO  - Nat. Chem. Biol.
VL  - 17
IS  - 11
PB  - Nature Portfolio
PY  - 2021
SN  - 1552-4450
ER  - 

TY  - JOUR
AB  - Virtually all aspects of cell biology are regulated by a ubiquitin code where distinct ubiquitin chain architectures guide the binding events and itineraries of modified substrates. Various combinations of E2 and E3 enzymes accomplish chain formation by forging isopeptide bonds between the C terminus of their transiently linked donor ubiquitin and a specific nucleophilic amino acid on the acceptor ubiquitin, yet it is unknown whether the fundamental feature of most acceptors—the lysine side chain—affects catalysis. Here, use of synthetic ubiquitins with non-natural acceptor site replacements reveals that the aliphatic side chain specifying reactive amine geometry is a determinant of the ubiquitin code, through unanticipated and complex reliance of many distinct ubiquitin-carrying enzymes on a canonical acceptor lysine. [Figure not available: see fulltext.]
AU  - Liwocha, J.*
AU  - Krist, D.T.*
AU  - van der Heden van Noort, G.J.*
AU  - Hansen, F.M.*
AU  - Truong, V.H.*
AU  - Karayel, O.*
AU  - Purser, N.*
AU  - Houston, D.*
AU  - Burton, N.*
AU  - Bostock, M.J.
AU  - Sattler, M.
AU  - Mann, M.*
AU  - Harrison, J.S.*
AU  - Kleiger, G.*
AU  - Ovaa, H.*
AU  - Schulman, B.A.*
C1  - 60740
C2  - 49504
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 272–279
TI  - Linkage-specific ubiquitin chain formation depends on a lysine hydrocarbon ruler.
JO  - Nat. Chem. Biol.
VL  - 17
PB  - Nature Research
PY  - 2021
SN  - 1552-4450
ER  - 

TY  - JOUR
AB  - An amendment to this paper has been published and can be accessed via a link at the top of the paper.In the version of this article previously published, several components of Fig. 1 were missing. In panels c and d, radicals were omitted from the compound structures; in panel e, the arrow going downward from arachidonate was partially removed. Additionally, the structure of ML094 in Fig. 4 was incorrect. The 1,3-cyclohexadiene ring on the south end of the molecule should be a naphthyl ring. The errors have been corrected in the HTML and PDF versions of the paper.
AU  - Conrad, M.
AU  - Pratt, D.A.*
C1  - 57775
C2  - 48101
SP  - 223-224
TI  - Publisher Correction: The chemical basis of ferroptosis (Nature Chemical Biology, (2019), 15, 12, (1137-1147), 10.1038/s41589-019-0408-1).
JO  - Nat. Chem. Biol.
VL  - 16
PY  - 2020
SN  - 1552-4450
ER  - 

TY  - JOUR
AB  - Lipid peroxidation underlies the mechanism of oxidative cell death now known as ferroptosis. This modality, distinct from other forms of cell death, has been intensely researched in recent years owing to its relevance in both degenerative disease and cancer. The demonstration that it can be modulated by small molecules in multiple pathophysiological contexts offers exciting opportunities for novel pharmacological interventions. Herein, we introduce the salient features of lipid peroxidation, how it can be modulated by small molecules and what principal aspects require urgent investigation by researchers in the field. The central role of non-enzymatic reactions in the execution of ferroptosis will be emphasized, as these processes have hitherto not been generally considered 'druggable'. Moreover, we provide a critical perspective on the biochemical mechanisms that contribute to cell vulnerability to ferroptosis and discuss how they can be exploited in the design of novel therapeutics.
AU  - Conrad, M.
AU  - Pratt, D.A.*
C1  - 57395
C2  - 47723
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 1137-1147
TI  - The chemical basis of ferroptosis.
JO  - Nat. Chem. Biol.
VL  - 15
IS  - 12
PB  - Nature Publishing Group
PY  - 2019
SN  - 1552-4450
ER  - 

TY  - JOUR
AB  - Phosphorylation of the carboxyl-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) governs stage-specific interactions with different cellular machines. The CTD consists of Y1S2P3T4S5P6S7 heptad repeats and sequential phosphorylations of Ser7, Ser5 and Ser2 occur universally at Pol II-transcribed genes. Phosphorylation of Thr4, however, appears to selectively modulate transcription of specific classes of genes. Here, we identify ten new Thr4 kinases from different kinase structural groups. Irreversible chemical inhibition of the most active Thr4 kinase, Hrr25, reveals a novel role for this kinase in transcription termination of specific class of noncoding snoRNA genes. Genome-wide profiles of Hrr25 reveal a selective enrichment at 3' regions of noncoding genes that display termination defects. Importantly, phospho-Thr4 marks placed by Hrr25 are recognized by Rtt103, a key component of the termination machinery. Our results suggest that these uncommon CTD kinases place phospho-Thr4 marks to regulate expression of targeted genes.
AU  - Nemec, C.M.*
AU  - Singh, A.K.*
AU  - Ali, A.*
AU  - Tseng, S.C.*
AU  - Syal, K.*
AU  - Ringelberg, K.J.*
AU  - Ho, Y.H.*
AU  - Hintermair, C.
AU  - Ahmad, M.F.*
AU  - Kar, R.K.*
AU  - Gasch, A.P.*
AU  - Akhtar, M.S.*
AU  - Eick, D.
AU  - Ansari, A.Z.*
C1  - 55077
C2  - 46025
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 123–131
TI  - Noncanonical CTD kinases regulate RNA polymerase II in a gene-class-specific manner.
JO  - Nat. Chem. Biol.
VL  - 15
IS  - 2
PB  - Nature Publishing Group
PY  - 2019
SN  - 1552-4450
ER  - 

TY  - JOUR
AB  - © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches—a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines—to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4–Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.
AU  - Doll, S.
AU  - Proneth, B.
AU  - Tyurina, A.A.*
AU  - Panzilius, E.
AU  - Kobayashi, S.
AU  - Ingold, I.
AU  - Irmler, M.
AU  - Beckers, J.
AU  - Aichler, M.
AU  - Walch, A.K.
AU  - Prokisch, H.
AU  - Trümbach, D.
AU  - Mao, G.*
AU  - Qu, F.*
AU  - Bayir, H.*
AU  - Füllekrug, J.*
AU  - Scheel, C.
AU  - Wurst, W.
AU  - Schick, J.
AU  - Kagan, V.E.*
AU  - Friedmann Angeli, J.P.F.
AU  - Conrad, M.
C1  - 49913
C2  - 41903
CY  - New York
SP  - 91-98
TI  - ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.
JO  - Nat. Chem. Biol.
VL  - 13
IS  - 1
PB  - Nature Publishing Group
PY  - 2017
SN  - 1552-4450
ER  - 

TY  - JOUR
AB  - Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.
AU  - Kagan, V.E.*
AU  - Mao, G.*
AU  - Qu, F.*
AU  - Friedmann Angeli, J.P.F.
AU  - Doll, S.
AU  - St. Croix, C.*
AU  - Dar, H.H.*
AU  - Liu, B.*
AU  - Tyurin, V.A.*
AU  - Ritov, V.B.*
AU  - Kapralov, A.A.*
AU  - Amoscato, A.A.*
AU  - Jiang, J.*
AU  - Anthonymuthu, T.*
AU  - Mohammadyani, D.*
AU  - Yang, Q.*
AU  - Proneth, B.
AU  - Klein-Seetharaman, J.*
AU  - Watkins, S.*
AU  - Bahar, I.*
AU  - Greenberger, J.*
AU  - Mallampalli, R.K.*
AU  - Stockwell, B.R.*
AU  - Tyurina, Y.Y.*
AU  - Conrad, M.
AU  - Bayir, H.*
C1  - 50293
C2  - 42077
CY  - New York
SP  - 81-90
TI  - Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis.
JO  - Nat. Chem. Biol.
VL  - 13
IS  - 1
PB  - Nature Publishing Group
PY  - 2017
SN  - 1552-4450
ER  -