<table><caption>Table 9. Regulators of Cobalt Signaling</caption><thead><tr><th>Chemical substance</th><th>Status*</th><th>Target/Effect</th><th>Pathology</th><th>Ref.</th></tr></thead><tbody><tr><td>CLI-095<br>Adenosylcobalamin<br>(Coenzyme B12)</td><td>Cell biology<br>tool<br>Clinical</td><td>Human Toll-like receptor 4<br>inhibitor<br>LRRK2 kinase</td><td>Soft tissue<br>necrosis,<br>osteolysis<br>PD</td><td>875<br>900</td></tr></tbody></table>

<figure><img src="image_92.png" /></figure>

interesting cytotoxic properties in cancer cells.⁸⁶⁰ This could potentially be exploited in cancer research and requires further studies. However, chromium itself has been reported to be carcinogenic, especially at higher exposures.⁸⁶¹ Importantly, high concentrations of chromium and nickel in electronic nicotine delivery systems have been associated with increased lung cancer risk.⁸⁶² Cobalt has been reported to stimulate PI3K/AKT signaling in oral squamous carcinoma cells.⁸⁶³ Nickel has been shown to have many effects on signaling in cancer cells.⁸⁶⁴ It can poison iron-dependent demethylases by replacing the redox-active iron catalyst, inactivating specific iron-dependent enzymes.⁸⁶⁵ Since these enzymes are involved in epigenetic regulation, nickel directly impacts the acquisition of distinct states of cancer cells. Nickel itself has also been shown to be carcinogenic and a driver of cancer progression.⁸⁶⁶

### 4.5.3.2. Other d-Block Metal Ion Signaling in Immunity and Inflammation.
Vanadium-containing drugs, so-called vanodrugs,⁸⁶⁶ have been shown to exhibit an effect on inflammation by affecting NF-κB and TLR signaling. Although, whether these drugs impact vanadium homeostasis and cellular functions remain unclear and explicit MoA are yet to be elucidated.⁸⁶⁷ Treatment of macrophages with vanadate resulted in stimulation of NF-κB and JNK signaling, suggesting a pro-inflammatory effect of vanadate and highlighting an effect on the acquisition of a pro-inflammatory cell states of macrophages.⁸⁶⁸ In another study, the pro-inflammatory effect of vanadate has been demonstrated in bronchoalveolar lavage cells in clinical settings.⁸⁶⁹ Kinases, such as cytosolic protein tyrosine kinase and others,⁸⁷⁰ were shown to be inhibited by vanadium and vanadium-containing compounds, in particular vanadate- and polyoxovanadate-containing compounds (Table 11), which can thus broadly affect cell signaling pathways involving phosphorylation.⁸⁷¹ Because of the effect of vanadium on phosphatases, vanadate has a positive effect on T cell activation via changes in tyrosine phosphorylation.⁸⁷² Thus, interference with signaling in immune cells by vanadium can provide control over cell states. Chromium can affect T and B lymphocyte function, macrophage function, and alter cytokine production, impacting immune responses.⁸⁷³ Chromium can inhibit the phagocytotic function of macrophages.⁸⁷⁴ Whether specific signaling pathways impact cell states requires further investigation. Cobalt ions can activate TLR4 generating an inflammatory response.⁸⁷⁵ This can be attenuated in vitro by the small molecule CLI-095, which can have an effect on soft tissue necrosis and osteolysis⁸⁷⁵ (Table 9). A pro-inflammatory response upon exposure to cobalt ions has also been observed in other cell types, including neutrophils, monocytes, and epithelial cells of the gut and kidney.⁸⁷⁶ Indeed, cobalt has been reported to induce an inflammatory state in macrophages, but underlying mechanisms driving cell state

transitions require further investigation.⁸⁷⁷ Nickel has been shown to act as a pro-inflammatory signaling element. Interestingly, zinc can inhibit nickel uptake and attenuate nickel-induced inflammation in THP-1 cells.⁸³⁵ Moreover, nickel promotes inflammatory responses by activating TLR4. The allergic and inflammatory reaction to nickel in some individuals has been explained with differential activation of specialized CD8+ cells.⁸⁷⁸,⁸⁷⁹ It is conceivable that nickel contributes to signaling pathways activating these cells, which require further studies. Nickel chelation has been successfully employed to treat chronic dermatosis, including compounds such as disulfiram, EDTA, and clioquinol⁸⁸⁰ (Table 10).

### 4.5.3.3. Other d-Block Metal Ion Signaling in Other Diseases.
Small molecules including EDTA, 2,3-disulfanylpropanol, and the clinically approved copper chelator D-penicillamine have been shown to reduce cellular vanadium levels⁸⁸¹⁻⁸⁸⁶ (Table 11). Vanadate can also replace phosphate in cells, and the effect of vanadium on insulin metabolism has encouraged research in this area.⁸⁸⁷ Vanadium-containing compounds can also mimic insulin⁸⁸⁸,⁸⁸⁹ and therefore exert a positive effect in diabetes. Such compounds include vanadyl sulfate (VOSO₄), bis(maltolato)oxovanadium(IV) (BMOV), and vanadyl-methylpicolinate complex (VO-MPA) among others⁸⁹⁰⁻⁸⁹³ (Table 11). These effects might also be translated to other clinical settings including cardiovascular diseases.⁸⁹⁴ The effect of chromium on amplifying insulin signaling also represents a promising line of research for the treatment of diabetes.⁸⁹⁵⁻⁸⁹⁷ Other small molecules that affect insulin-resistance in vitro including chromium complexes have been documented⁸⁹⁷⁻⁸⁹⁹ (Table 12) and represent an interesting starting point for the development of therapeutic strategies. Mutations in leucine-rich repeat kinase 2 (LRRK2) have been associated with the progression of PD. The cobalt-containing vitamin B12 is an allosteric inhibitor of LRRK2 and has been shown to reduce neurotoxicity in rodent models of PD⁹⁰⁰ (Table 9). In contrast, cobalt ions have been shown to be neurotoxic⁹⁰¹ and to promote PD, presumably involving the production of ROS. However, explicit mechanisms are not fully understood.⁹⁰² Nickel has been reported to drive cardiovascular and kidney diseases and lung fibrosis.⁹⁰³ The exact mechanisms underlying these effects remain to be characterized. Deficiency of the molybdenum cofactor Moco is found in a rare genetic disease that leads to early development defects and contributes to neurodegeneration.⁹⁰⁴ A treatment based on precursor Z/cPMP/fosdenopterin (Table 13) has been used for therapeutic intervention.⁸⁴²,⁹⁰⁵,⁹⁰⁶

<footnote>*https://www.fda.gov, https://clinicaltrials.gov</footnote>
<table><caption>Table 10. Regulators of Nickel Signaling</caption><thead><tr><th>Chemical substance</th><th>Status*</th><th>Target/Effect</th><th>Pathology</th><th>Ref.</th></tr></thead><tbody><tr><td>Zn<sup>2+</sup></td><td>Cell biology tool</td><td>Modulation of Ni<sup>2+</sup> uptake by inflammatory cells</td><td>Inflammation</td><td>835</td></tr><tr><td>diglycyl- histidine-N-methylamide</td><td>Cell biology tool</td><td>Chelating agent for Nickel</td><td>Toxicology of nickel</td><td>836,907</td></tr><tr><td>Disulfiram</td><td>FDA Clinical</td><td>Ni chelation</td><td>Chronic dermatoses</td><td>880</td></tr><tr><td>Calcium carbonate</td><td>Clinical</td><td>Ni chelation</td><td>Chronic dermatoses</td><td>880</td></tr><tr><td>EDTA</td><td>Clinical</td><td>Ni chelation</td><td>Chronic dermatoses</td><td>880</td></tr><tr><td>Clioquinol</td><td>FDA Clinical</td><td>Ni chelation</td><td>Chronic dermatoses</td><td>880</td></tr><tr><td>Sodium diethyldithiocarbamate</td><td>Clinical</td><td>Ni chelation</td><td>Ni(CO)<sub>4</sub> poisoning</td><td>908</td></tr><tr><td>D-Penicillamine</td><td>Clinical</td><td>Ni chelation</td><td>Ni(II) poisoning</td><td>908</td></tr><tr><td>Trientine</td><td>FDA Clinical</td><td>Ni chelation</td><td>Ni(II) poisoning</td><td>908</td></tr><tr><td>DMG</td><td>Cell biology tool</td><td>Ni chelation<br>Ni chelation/inhibition of human amyloid beta peptide</td><td>Multi-drug resistant enteric pathogens AD</td><td>909,910</td></tr><tr><td>3-hydroxyflavone</td><td>Cell biology tool</td><td>Ni chelation</td><td>Ni therapy</td><td>911</td></tr><tr><td>Deferiprone</td><td>FDA Clinical</td><td>Ni chelation</td><td>Ni therapy</td><td>911</td></tr><tr><td>Maltol</td><td>FDA Clinical</td><td>Ni chelation</td><td>Ni therapy</td><td>911</td></tr><tr><td>Mg(II) carbonate</td><td>Cell biology tool</td><td>Inhibition of renal carcinogenesis</td><td>Renal carcinogenesis induced by Ni<sub>3</sub>S<sub>2</sub></td><td>912</td></tr><tr><td>Metallic powder Fe(0) or Fe(III)</td><td>Cell biology tool</td><td>Inhibition of carcinogenesis</td><td>Carcinogenesis induced by Ni<sub>3</sub>S<sub>2</sub></td><td>912</td></tr><tr><td>[Ni(L)(D-CAM)(H<sub>2</sub>O)]n Metal drug-gel particle</td><td>Cell biology tool</td><td>Drug carrier</td><td>Cervical cancer</td><td>913</td></tr></tbody></table>

## 5. REMARKS

Metals exhibit a diverse range of chemistries including Lewis acid catalysis, redox, and supramolecular properties. The cell has evolved around these chemistries to mediate signal transduction while dealing with potentially detrimental reactions inherent to the reactivity of metals. This notion is best exemplified by the higher iron load required for cells to promote epigenetic reprogramming via oxidative demethylation of histone proteins, which concomitantly drives oxidation of lipids and confers

vulnerability to ferroptosis.⁵¹⁵ Thus, cells have developed machineries to repair oxidized membranes, enabling them to exploit iron to adapt to their environment.

Here, we have discussed the essential roles of metals in the biology of the cell. We have documented current knowledge on mechanisms regulating cellular metal homeostasis, including how metals are internalized by, distributed and stored within, and exported outside of the cell. We have described the multifaceted chemical roles of metals in transducing information inside the cell in normal physiology and how this regulation can

<footnote>*https://www.fda.gov, https://clinicaltrials.gov</footnote>
<table><caption>Table 11. Regulators of Vanadium Signaling</caption><thead><tr><th>Chemical substance</th><th>Status*</th><th>Target/Effect</th><th>Pathology</th><th>Ref.</th></tr></thead><tbody><tr><td>2,3-disulfanylpropanol</td><td>Cell biology tool</td><td>Vanadium</td><td>Vanadium intoxication/ poisoning</td><td>881</td></tr><tr><td>L-cysteine</td><td>Clinical</td><td>Vanadium</td><td>Vanadium intoxication/ poisoning</td><td>881</td></tr><tr><td>D-penicillamine</td><td>Clinical</td><td>Vanadium</td><td>Vanadium intoxication/ poisoning</td><td>881,882</td></tr><tr><td>EDTA</td><td>Clinical</td><td>Vanadium</td><td>Vanadium intoxication/ poisoning</td><td>881,882</td></tr><tr><td>Ascorbic acid</td><td>Clinical</td><td>Vanadium</td><td>Vanadium intoxication/ poisoning</td><td>881,886</td></tr><tr><td>Meso-2,3-diaminosuccinic acid</td><td>Cell biology tool</td><td>Vanadium</td><td>Vanadium intoxication/ poisoning</td><td>881,914-916</td></tr><tr><td>2,3-disulfanylpropane-1-sulfonic acid</td><td>Cell biology tool</td><td>Vanadium</td><td>Vanadium intoxication/ poisoning</td><td>881,914-916</td></tr><tr><td>Tiron (4,5-dihydroxy-1,3-benzene-disulfonic acid)</td><td>Cell biology tool</td><td>Vanadium</td><td>Vanadium intoxication/ poisoning</td><td>883,884,886,917</td></tr><tr><td>2-mercaptosuccinic acid</td><td>Cell biology tool</td><td>Vanadium</td><td>Vanadium intoxication/ poisoning</td><td>886,917</td></tr><tr><td>Vanadium-acetylacetonate</td><td>Cell biology tool</td><td>Insulin mimic</td><td>Diabetes, Insulin signaling cascade</td><td>889,918</td></tr><tr><td>L-Glu(γ)HXM (L-glutamic acid (γ) monohydroxamate)</td><td>Cell biology tool</td><td>Insulin mimic</td><td>Diabetes, glucose metabolism</td><td>889,919</td></tr><tr><td>Vanadate</td><td>Cell biology tool</td><td>Insulin mimic</td><td>Diabetes, Insulin signaling cascade</td><td>890</td></tr><tr><td>NaVO<sub>3</sub></td><td>Cell biology tool</td><td>Insulin mimic</td><td>Diabetes, Insulin signaling cascade</td><td>890</td></tr><tr><td>Sodium metavanadate</td><td>Cell biology tool</td><td>Insulin mimic</td><td>Diabetes, Insulin signaling cascade</td><td>890</td></tr><tr><td>VOSO<sub>4</sub> vanadyl sulphate</td><td>Cell biology tool</td><td>Insulin mimic: Vanadyl complexation</td><td>Diabetes, Insulin signaling cascade</td><td>890-892</td></tr></tbody></table>
<table><caption>Table 11. continued</caption><tr><td>BMOV</td><td>Cell biology tool</td><td>Insulin mimic: Vanadyl complexation</td><td>Diabetes, Insulin signaling cascade</td><td>890,893</td></tr><tr><td>VO-MPA</td><td>Cell biology tool</td><td>Insulin mimic: Peroxovanadate complexation</td><td>Diabetes, Insulin signaling cascade</td><td>890,920</td></tr><tr><td>pV(phen)</td><td>Cell biology tool</td><td>Insulin mimic</td><td>Diabetes, glucose metabolism</td><td>921,922</td></tr><tr><td>BEOV</td><td>Cell biology tool</td><td>Vanadium Compounds as PTP Inhibitors</td><td>Diabetes, cancer</td><td>923</td></tr><tr><td>Vanadium Compounds</td><td>Cell biology tool</td><td>Vanadium Compounds as PTP Inhibitors</td><td>Diabetes, cancer</td><td>923</td></tr></table>

<table><caption>Table 12. Regulators of Chromium Signaling</caption><thead><tr><th>Chemical substance</th><th>Status*</th><th>Target/Effect</th><th>Pathology</th><th>Ref.</th></tr></thead><tbody><tr><td>Chromium picolinate<br>Chromium complexes<br>Chromium supplementation</td><td>Cell biology tool</td><td>Glucose and lipid metabolism</td><td>Type 2 diabetes, Insulin resistance</td><td>897-899</td></tr><tr><td>NAC</td><td>Cell biology tool</td><td>Cr chelation</td><td>Cr intoxication</td><td>924,925</td></tr><tr><td>TDTA</td><td>Cell biology tool</td><td>Cr chelation</td><td>Cr intoxication</td><td>924,926</td></tr><tr><td>Ascorbic acid</td><td>Cell biology tool</td><td>Cr chelation</td><td>Cr intoxication</td><td>924,927,928</td></tr><tr><td>TTHA</td><td>Cell biology tool</td><td>Cr chelation</td><td>Cr intoxication</td><td>926</td></tr><tr><td>EDDHA</td><td>Cell biology tool</td><td>Cr chelation</td><td>Cr intoxication</td><td>929</td></tr><tr><td>NTA</td><td>Cell biology tool</td><td>Cr chelation</td><td>Cr intoxication</td><td>929</td></tr><tr><td>CDTA</td><td>Cell biology tool</td><td>Cr chelation</td><td>Cr intoxication</td><td>930,931</td></tr><tr><td>Pre-treatment with DFO</td><td>Cell biology tool</td><td>Cr chelation</td><td>Cr intoxication</td><td>930,931</td></tr></tbody></table>

<footnote>*https://www.fda.gov, https://clinicaltrials.gov</footnote>

<footnote>*https://www.fda.gov, https://clinicaltrials.gov</footnote>
<table><caption>Table 13. Regulators of Molybdenum Signaling</caption><thead><tr><th>Chemical substance</th><th>Status*</th><th>Target/Effect</th><th>Pathology</th><th>Ref.</th></tr></thead><tbody><tr><td>Precursor Z/cPMP/ Fosdenopterin</td><td>FDA</td><td>Molybdenum cofactor deficiency<br>Lack of Moco biosynthesis</td><td>Feeding difficulties, severe and progressive neurologic abnormalities, and dysmorphic features of the brain and head</td><td>841,905,906,932</td></tr><tr><td>Mo-biofortified</td><td>Clinical</td><td>Gut-bone axis</td><td>Bone homeostasis and osteoporosis in the elderly</td><td>933</td></tr></tbody></table>

contribute to diseases, in particular by promoting the acquisition of distinct cell properties and states. Based on their electron configuration, which defines their position in the periodic table, metals are found in the cell as crystalline forms or positively charged ions, having a propensity to act as counterions to balance charges in the cell, to promote conformational changes of biomolecules acting as cofactors that modulate function, or to mediate otherwise inefficient chemical reactions operating as catalysts.

Unlike organic biomolecules, such as proteins, nucleic acids, lipids, and glycans, metal ions are not synthesized in the cell but acquired from external sources such as nutrients. These species are smaller in size, conferring faster diffusion rates within the cell compared to biopolymers and exist in various oxidation states, being found either as free or bound species,²¹⁶ making these chemical entities difficult to track within and outside of the cell. The literature clearly shows that multiple import and export mechanisms exist for metal ions and that these mechanisms are often not specific for a given metal. Furthermore, distinct metals can exhibit redundant properties. Thus, manipulating a given metal selectively in the cell to investigate its role in disease-relevant settings remains a challenging endeavor. Nature itself, which relies on fundamental principles of physical chemistry, has not been able to achieve complete selectivity for specific metals, which raises the question of whether we, the scientists, can invent new strategies and develop smarter chemistries to achieve selective control over metals in the cell. In other words, can we chemically target a given metal without affecting the biology of others? Can we manipulate a single function of a given metal selectively?

Our knowledge of the biology of metals is still in its infancy. For example, iron has been shown to fuel the activity of enzymes in the nucleus to promote epigenetic reprogramming and cell adaptation,⁴⁴⁶ yet it remains unknown how iron traffics to the nucleus where chromatin is localized. Copper(II) has been shown to catalyze NAD(H) redox cycling in mitochondria, enabling activation of immune cells in acute inflammation settings and to regulate the acquisition of a pro-metastatic state of cancer cells,¹³ but whether this is assisted by a protein stabilizing the transition state of this copper-catalyzed reaction remains unknown. Future efforts should be dedicated to identifying missing pieces in how cells control metal homeostasis. To this end, developing new probes and technologies to map out sites of action of metals in the cell, in an oxidation-state-specific manner, will be essential to our understanding of their roles in cell signaling. This may reveal new features that can be exploited for the development of small molecule modulators of

cell signaling, either through direct metal targeting or alternatively acting upstream or downstream on associated signaling effectors. Another layer of complexity for the development of drugs involves our capacity to target specific tissues and specific cell types, in particular, the cells exhibiting a diseased state or more generally cells contributing to the disease or a pathological condition. How metal homeostasis is regulated at the level of specific tissues and between distinct cell types within a given tissue is complex and not fully understood, raising again the challenge of how to selectively target a metal ion signaling axis in a given cell type or tissue.

Discovery-driven approaches have been instrumental in delineating metal ion signaling pathways and the identification of related druggable targets. For example, Schreiber and Crabtree have illuminated calcium signaling partly by elucidating the MoA of complex biologically active small molecules, namely FK-506 and cyclosporin A,²²⁻²⁴,²⁶ which has prompted interest into the development of small molecule-proximity inducers and given rise to the field of molecular glues.⁹³⁴ Notably, these compounds (Table 4) inhibit T cell activation by forming complexes with distinct immunophilins that bind to and inactivate the calcium- and calmodulin-dependent phosphatase calcineurin.²²⁻²⁴,²⁶ These classes of compounds are potent immunosuppressors that have been used for the clinical management of organ transplants and other immune diseases. Importantly, calcium signaling is inhibited independently of direct calcium ion targeting. Similarly, studying the MoA of trichostatin A and trapoxin A (Table 8), Schreiber and co-workers have identified mammalian HDACs, contributing to the rise of epigenetics.¹⁵ Directly targeting zinc in the active site of HDACs using hydroxamic acid-containing small molecules has been shown to alter chromatin, impacting transcriptional programs and tumor progression. This pioneering work promoted the development of new anticancer therapeutics, demonstrating the druggable nature of this class of enzymes and raising the question of whether a given HDAC can be targeted selectively and at specific genomic loci.⁸²⁶,⁹³⁵ A similar rationale has been applied for the design of iron-dependent demethylase inhibitors, which can inactivate iron in the enzyme active site, with little specificity toward a given demethylase.⁵³¹,⁹³⁶ Nevertheless, these studies emphasize the druggable nature of metalloenzymes targeting the metal active site. While targeting of free metal ions has been documented, notably with the use of the deferoxamine (Table 6) for the treatment of β-thalassemia and myelodysplastic syndrome, little is known about the sites of action of iron chelators in the cell and how, mechanistically, depleting iron confers therapeutic benefits

<footnote>*https://www.fda.gov, https://clinicaltrials.gov</footnote>
with manageable off-target effects. In contrast, a small molecule screen coupled to molecular editing yielded small molecules, such as ironomycin, that directly target iron(II) in endolysosomes of DTP cancer cells and trigger ferroptosis in preclinical models of metastatic cancers.<sup>511,514,516</sup> This work identified lysosomal iron as a druggable target in difficult-to-treat cancers. In another study, a phenotypic screen informed the design of the metformin dimer supformin capable of selective mitochondrial copper(II) targeting, antagonizing macrophage activation and preventing sepsis in preclinical models of acute inflammation.<sup>13</sup> This work identified mitochondrial copper(II) as a driver of inflammation and a druggable target.

These studies have provided solid evidence that direct targeting of specific metals with small molecules, whose increased uptake is causal to the disease, can be achieved and confer therapeutic benefits. Hypothesis-driven approaches together with the rise of artificial intelligence and machine learning may represent an effective route forward, potentially enabling faster and more systematic production of biologically active small molecules and metal ion signaling drugs.<sup>937,938</sup> It is not clear; however, whether these strategies can surpass discovery-based phenotypic approaches.<sup>36</sup> Small molecules have illuminated cell signaling pathways involving metals and demonstrated that some of these processes can be targeted with therapeutic value. While no general rule can be established at this point and much remains to be learned in this area, it is fair to say that metal ion signaling regulators are undruggable until someone drugs them.

## AUTHOR INFORMATION

### Corresponding Author

Raphaël Rodriguez – Institut Curie, CNRS, INSERM, PSL
Research University, 75005 Paris, France; orcid.org/0000-0001-7668-446X; Email: raphael.rodriguez@curie.fr

### Authors

Sebastian Müller – Institut Curie, CNRS, INSERM, PSL
Research University, 75005 Paris, France

Ludovic Colombeau – Institut Curie, CNRS, INSERM, PSL
Research University, 75005 Paris, France

Stéphanie Solier – Institut Curie, CNRS, INSERM, PSL
Research University, 75005 Paris, France; Université Paris-Saclay, UVSQ, 78180 Montigny-le-Bretonneux, France

Fabien Sindikubwabo – Institut Curie, CNRS, INSERM, PSL
Research University, 75005 Paris, France

Tatiana Cañeque – Institut Curie, CNRS, INSERM, PSL
Research University, 75005 Paris, France; orcid.org/0000-0002-1110-0643

Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.chemrev.4c00577

### Author Contributions

CRediT: **Raphaël Rodriguez** conceptualization, funding acquisition, methodology, project administration, supervision, writing - original draft, writing - review & editing; **Sebastian Müller** writing - original draft, writing - review & editing; **Ludovic Colombeau** writing - original draft, writing - review & editing; **Stéphanie Solier** writing - original draft, writing - review & editing; **Fabien Sindikubwabo** writing - review & editing; **Tatiana Cañeque** writing - original draft, writing - review & editing.

## Notes

The authors declare no competing financial interest.

## Biographies

Raphaël Rodriguez is a Research Director at the CNRS and a Principal Investigator at Institut Curie where he holds the Skłodowska-Curie Chair of Chemical Biology. He acquired the knowledge of chemistry and biology in the United Kingdom under the mentorships of Sir J. E. Baldwin, S. Balasubramanian, and S. P. Jackson from 2004 to 2012. He then established the Biomedicine Laboratory in France to investigate the molecular bases underlying cancer metastasis and inflammation. Together with his lab co-workers, he discovered the central role of metals as regulators of cell adaptation and elucidated basic cellular mechanisms of ferroptosis. He has received a Knighthood of the National Order of Merit from J.-M. Lehn and a few accolades including the Liliane Bettencourt Prize for Life Sciences and the Tetrahedron Young Investigator Award in Bioorganic and Medicinal Chemistry.

Sebastian Müller graduated from Durham University in the United Kingdom for his undergraduate education in Chemistry and Biology in 2006. He earned his Ph.D. in Chemistry in 2011 from the University of Cambridge under the supervision of Sir S. Balasubramanian. He then continued his career as a Postdoctoral Research Associate in the Almouzni lab at Institut Curie, where he worked on chromatin biology from 2011 to 2016. He then joined the Rodriguez lab, where he now holds a Senior Scientist position at INSERM. He studies the roles of metal ions in cancer.

Ludovic Colombeau received a Ph.D. degree in Chemistry in 2006 from the University of Limoges. From 2006 to 2018, he pursued his postdoctoral training at the University of Sherbrooke and in France. He joined the Rodriguez lab in 2019 as Research Engineer, where he focuses on the design and synthesis of biologically active small molecules.

Stéphanie Solier received a Ph.D. degree from the University of Dijon, where she studied the role of topoisomerases in alternative splicing. She trained as a Postdoctoral Scientist at the National Cancer Institute in Bethesda, where she studied the crosstalk between DNA damage and cell death, identifying the γ-H2AX apoptotic ring. She then consolidated her expertise in Cancer Biology at Institut Gustave Roussy, where she found that caspase inhibition could be an efficient strategy to modulate macrophage polarization in damaged tissues. She joined the Rodriguez lab in 2019 as a Postdoctoral Scientist and now holds an Assistant Professor position. She studies the roles of metal ions in immunity.

Fabien Sindikubwabo received a Ph.D. degree in Physiology, Physiopathology and Pharmacology in 2017 from the University of Grenoble Alpes. He investigated how HDAC3-mediated epigenetic mechanisms regulate gene expression in *T. gondii* and drives pathogenesis. He trained as a Postdoctoral Scientist at Institut Curie in the Rodriguez lab, where he now holds a Senior Scientist position at the CNRS. He studies the roles of metal ions in cancer.

Tatiana Cañeque obtained a European Ph.D. degree in Chemistry in 2010 from the University of Alcalá. She trained as a Postdoctoral Scientist at ICSN in the Malacria lab. Since 2018, she holds a Research Engineer position at the CNRS in the Rodriguez lab. Her research interests include transition metal catalysis, total synthesis of natural products, and the targeting of metal ions in diseases.

## ACKNOWLEDGMENTS

We thank the CNRS, INSERM, the European Research Council, Ligue Contre le Cancer, Agence Nationale de la Recherche,
Institut National du Cancer, Fondation Bettencourt-Schueller, Fondation Charles Defforey, Institut de France and the Klaus Grohe Foundation for financial support. We thank C. Gaillet for proofreading this manuscript. R.R. expresses his gratitude to J.-M. Lehn and S.L. Schreiber.

ABBREVIATIONS

α-KG = α-ketoglutarate
Aβ = amyloid beta
ABC = ATP-binding cassette family
AD = Alzheimer's disease
ADP = adenosine diphosphate
AKT = serine/threonine protein kinase
ALDH = aldehyde dehydrogenase
ALDH1 = aldehyde dehydrogenase 1
aMDM = activated monocyte-derived macrophages
AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepro-pionic acid receptor
AMP = adenosine monophosphate
AMPK = AMP-activated protein kinase
AP-1 = activating protein-1
APLP1 = amyloid beta precursor like protein 1
ASIC = acid-sensing ion channel
ATOX1 = antioxidant 1 copper chaperone
ATP = adenosine triphosphate
ATP13A2 = ATPase cation transporting 13A2
ATP7A = copper-transporting ATPase 1
ATP7B = copper-transporting ATPase 2
Bax = Bcl-2-associated protein x
Bcl-2 = B-cell lymphoma 2
BMP6 = bone morphogenetic protein 6
BMPR = bone morphogenetic protein receptor
BRAF = v-raf murine sarcoma viral oncogene homologue B1
CaM = calmodulin
cAMP = cyclic adenosine monophosphate
CaSR = calcium-sensing receptor
Cas = CRISPR associated protein
Cav3.1/3.2/3.3 = T-type voltage-gated calcium channel 3.1/3.2/3.3
CAX = cation/proton exchanger
Cbl = cobalamin
CCS = copper chaperone for superoxide dismutase
CD44 = cluster of differentiation 44
CDC25C = cell division cycle 25C
Cdk1 = cyclin-dependent kinase 1
cGAS = protein cyclic GMP-AMP synthase
CK2 = casein kinase 2
CLDN16/19 = claudin-16/19
CNNM3/4 = cyclin and CBS domain divalent metal cation transport mediator 3/4
CoA = coenzyme A
COX = cytochrome c oxidase
CRAC = calcium release-activated calcium channel
CREB = cyclic-AMP responsive element-binding protein
CRISPR = clustered regularly interspaced short palindromic repeats
CSCs = cancer stem cells
c-src = cellular src
Ctr1/2 = copper transporter 1/2
Cyt c = cytochrome c
DAG = diacylglycerol
DAT1 = dopamine transporter 1

DC_AC50 = 3-amino-N-(2-bromo-4,6-difluorophenyl)-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxamide
DFO = deferoxamine
DFX = deferasirox
DHBA = dihydroxybenzoic acid
DLAT = dihydrolipoyl acetyltransferase
DLST = dihydrolipoyl succinyltransferase
DMT1 = divalent metal transporter 1
DNA = deoxyribonucleic acid
dsDNA = double-stranded DNA
DTP = drug-tolerant persister
DTPA = diethylenetriaminepentaacetic acid
ECM = extracellular matrix
EGFR = epithelial growth factor receptor
EMT = epithelial-to-mesenchymal transition
ENaC = epithelial sodium channel
ER = endoplasmic reticulum
ERFE = erythroferrone
ERK = extracellular-signal-regulated kinase
ERK1/2 = extracellular-signal-regulated kinase 1/2
ERMES = endoplasmic reticulum mitochondria encounter structure
ESCC = esophageal squamous cell carcinoma
ETC = electron transport chain
FasL = Fas ligand
FHA = forkhead-associated domain
FIH1 = factor inhibiting HIF-1
FSP1 = ferroptosis suppressor protein 1
FTH1 = ferritin heavy chain
FTL = ferritin light chain
FTO = fat mass and obesity-associated protein
G4 = G-quadruplex
GABA = γ-aminobutyric acid
GABA<sub>A</sub> = γ-aminobutyric acid type A
GLUTs = glucose transporters
GPCR = G protein-coupled receptor
GPX4 = glutathione peroxidase 4
GSH = glutathione
GSK-3 = glycogen synthase kinase 3
GSSG = glutathione disulfide
H3K9me2 = histone 3 lysine 9 dimethyl
H3K27me3 = histone 3 lysine 27 trimethyl
HAMP = hepcidin antimicrobial peptide
HAT = histone acetyltransferase
HBED = N,N'-di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid
HCC = hepatocellular carcinoma
HCN = hyperpolarization-activated cyclic nucleotide-gated channel
HD = Huntington's disease
HDAC = histone deacetylase
HIF = hypoxia-inducible transcription factor
HIF-1 = hypoxia-inducible transcription factor-1
HIF-1α/1β/2α = hypoxia-inducible transcription factor-1α/1β/2α
HIV-1 = human immunodeficiency virus type 1
HN1L = hematological and neurological expressed 1-like protein
HRE = hypoxia-response element
ICP-MS = inductively coupled plasma-mass spectrometry
IFN = interferon
IFN-λ3/γ = interferon lambda3/gamma
IFNLR1 = interferon lambda receptor 1

IKK = IκB kinase

IKKβ = IκB kinase β

IL-1β/1-4/2/17 = interleukin-1β/1-4/2/17

IP₃ = inositol triphosphate

IP₃R = IP3 receptor

IRE = iron-responsive element

IRF3/7 = interferon regulatory factor 3/7

IRP = iron regulatory protein

IRP1/2 = iron regulatory protein 1/2

JAK = Janus kinase

JNK = c-Jun N-terminal kinase

K.Ca3.1 = calcium-activated potassium channel 3.1

KDM3B/6A/6B = Histone lysine demethylase 3B/6A/6B

KHE = potassium/proton exchanger

Kir = inward-rectifier potassium channel

K-ras = Kirsten rat sarcoma virus

Kv = potassium voltage-gated channel

LCC-12 = lipophilic copper clamp 12

LCN2 = lipocalin-2

LCN2R = lipocalin-2 receptor

LCS-1 = lung cancer screen 1

LFA-1 = lymphocyte function-associated antigen 1

LRRK2 = leucine-rich repeat kinase 2

LTCC = L-type calcium channel

MagT1 = magnesium transporter 1

MAPK = mitogen-activated protein kinase

MCM = methyl malonyl CoA mutase

MCOLN1 = mucolipin-1

MCU = mitochondrial calcium uniporter

MD = Menkes disease

MEK = mitogen-activated protein kinase kinase

MEK1/2 = mitogen-activated protein kinase kinase 1/2

METAP1 = methionine aminopeptidase 1

MICU1 = mitochondrial calcium uptake 1

mitoBK<sub>Ca</sub> = mitochondrial large-conductance calcium-regulated potassium channel

mitoK<sub>ATP</sub> = mitochondrial ATP-regulated potassium channel

mitoKv = mitochondrial potassium voltage-gated channel

ML-9 = 1-(5-chloronaphthalen-1-yl)sulfonyl-1,4-diazepane

ML-SA1 = 2-[2-oxo-2-(2,2,4-trimethyl-3,4-dihydroquinolin-1-yl)ethyl]isoindole-1,3-dione

MMP-9 = matrix metalloproteinase 9

MoA = mechanism of action

Moco = molybdenum cofactor

MRE = metal response element

mRNA = messenger RNA

MRS-1844 = N-methylnitrendipine

MRS-1845 = N-propargylnitrendipine

MRS2 = mitochondrial RNA splicing 2

MS = methionine synthase

MT = metallothionein

MT1/2/3 = metallothionein 1/2/3

MTF-1 = metal response element transcription factor-1

mTOR = mammalian target of rapamycin

mTORC1 = mammalian target of rapamycin complex 1

MVBs = multivesicular bodies

NAADP = nicotinic acid adenine dinucleotide phosphate

NAD+ = nicotinamide adenine dinucleotide

NADH = nicotinamide adenine dinucleotide hydride

NALCN = sodium leak channel non-selective

naMDM = non activated monocyte-derived macrophages

NASH = non alcoholic steatohepatitis

NCBn1 = sodium/bicarbonate cotransporter

NCKX = potassium-dependent sodium/calcium exchanger

NCLX = mitochondrial sodium/calcium exchanger

NCOA4 = nuclear receptor coactivator 4

NCX = sodium/calcium exchanger

NDRG1 = N-myc downstream regulated 1

NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells

NFAT = nuclear factor of activated T cells

NFAT5 = nuclear factor of activated T cells 5

NHE = sodium/proton exchanger

NIPA1-4 = nonimprinted in Prader-Willi/Angelman syndrome 1-4

NIS = sodium/iodide symporter

NKCC = sodium/potassium/chloride cotransporter

NLRP3 = nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3

NMDAR = N-methyl-D-aspartate receptor

NRAMP = natural resistance-associated macrophage protein 1

NRF2 = nuclear factor erythroid 2-related factor 2

NSCLC = non small cell lung cancer

ORAI = calcium release-activated calcium modulator

OSCC = oral squamous cell carcinoma

P2X4R = purinergic P2X receptor 4

P2X7R = purinergic P2X receptor 7

PARK7 = Parkinson disease protein 7

PCBP1/2 = poly(rC)-binding protein 1/2

PD = Parkinson's disease

PDE3B = phosphodiesterase 3B

PDZD11 = PDZ domain-containing protein 11

PHD = iron-dependent prolyl hydroxylase

PHF8 = plant homeodomain (PHD) finger protein 8

Pi = inorganic phosphate

PI3K = phosphatidylinositol-3 kinase

pIRF3 = phosphorylated interferon regulatory factor 3

Pit1 = inorganic phosphate transporter 1

PKC = protein kinase C

PLC = phospholipase C

PLCγ = phospholipase C gamma

PLEKHA = Pleckstrin homology domain containing family A

PLEKHA 5/6/7 = Pleckstrin homology domain containing family A 5/6/7

PMCA = plasma membrane calcium ATPase

pNFAT = phosphorylated nuclear factor of activated T cells

pNF-κB = phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells

PTP = protein tyrosine phosphatases

PTP1b = protein-tyrosine phosphatase 1b

pVHL = Von Hippel-Lindau tumor suppressor

Ras = rat sarcoma virus

RNA = ribonucleic acid

ROS = reactive oxygen species

RyR = ryanodine receptor

Sco1/2 = cytochrome c oxidase assembly protein 1/2

SERCA = sarcoplasmic/endoplasmic reticulum calcium ATPase

SGLT = sodium/glucose cotransporter

SLC24A5 = solute carrier family 24 member 5

SLC25A3 = solute carrier family 25 member 3

SLC25A5 = solute carrier family 25 member 5

SLC30A10 = solute carrier family 30 member 10

SLC39A14 = solute carrier family 39 member 14
SLC41A1 = solute carrier family 41 member 1

SLC41A2 = solute carrier family 41 member 2

SLC41A3 = solute carrier family 41 member 3

SLC46A3 = solute carrier family 46 member 3

SMAD = suppressor of mothers against decapentaplegic

SMAD1/5/8 = mothers against decapentaplegic homologue
1/5/8

SOD = superoxide dismutase

SOD1/2 = superoxide dismutase 1/2

SPCA = secretory pathway calcium ATPase

SPCA1/2 = secretory pathway calcium-ATPase pump type
1/2

SR = sarcoplasmic reticulum

STAT = signal transducer and activator of transcription

STAT3 = signal transducer and activator of transcription 3

STEAP = 6-transmembrane epithelial antigen of prostate

STEAP4 = 6-transmembrane epithelial antigen of prostate 4

STIM = stromal interaction molecule

STING = stimulator of interferon genes

TEPA = tetraethylenepentamine

TET = ten-11 translocation

Tf = transferrin

TfR1 = transferrin receptor

TF = transcription factor

TGF = transforming growth factor

TGF-β = transforming growth factor beta

TIMP1 = tissue inhibitor of metalloprotease-1

TLR = Toll-like receptor

TLR4 = Toll-like receptor 4

TMEM94/16S/17S = transmembrane protein 94/16S/17S

TMPRSS6 = transmembrane serine protease 6

TNBC = triple-negative breast cancer

TPC = two-pore channel

TRP = transient receptor potential

TRPA1 = transient receptor potential ankyrin 1

TRPC = transient receptor potential canonical

TRPC1/3–6 = transient receptor potential canonical 1/3–6

TRPM2/6/7/8 = transient receptor potential melastatin 2/
6/7/8

TRPML = transient receptor potential mucolipin

TRPML1 = transient receptor potential mucolipin 1

TRPP2 = transient receptor potential polycystin-2

TRPV1/2/3/4/6 = transient receptor potential vanilloid type
1/2/3/4/6

TTHA = triethylenetetramine hexaacetic acid

TTM = tetrathiomolybdate

ULK1/2 = UNC51-like kinase-1/2

UTRs = untranslated regions

VDAC = voltage-dependent anion channel

VEGFR = vascular endothelial growth factor receptor

VGSC = voltage-gated sodium channel

WD = Wilson's disease

Wnt = wingless/integrated

ZIP = ZRT/IRT-like protein

ZIP1–11/13/14/16 = ZRT/IRT-like protein 1–11/13/14/
16

ZNFs = zinc-finger proteins

ZNG1 = zinc-regulated GTPase metalloprotein activator 1

ZnT = zinc transporter

ZnT1/2/4/5/6/7/9/10 = zinc transporter 1/2/4/5/6/7/9/
10

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