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Multifaceted roles for persulfide species in redox chemical biology

Nature Chemical Biology (2026)Cite this article

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Abstract

Reactive sulfur species (RSS) are increasingly recognized as important bioactive agents across phyla. Application of newly developed chemical tools, detection methods and multi-omics techniques has uncovered new and specific roles of endogenous RSS and revealed that a number of biological actions previously attributed to reactive oxygen species or reactive nitrogen species can also be mediated by RSS. This Review describes the versatile chemical biology of RSS with focus on persulfide formation on cysteine residues. We examine their pro-oxidant and antioxidant capacities, involvement in redox signaling and metabolic pathways, stress responses, and their role in the pathophysiology of major disease groups, including cardiovascular and neurodegenerative diseases and cancer. We also provide a critical discussion of available detection methods and potential pharmacological and genetic approaches to adjusting persulfide levels. We cover current knowledge and its limitations, along with practical recommendations for advancing persulfide-based therapeutic interventions.

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Fig. 1: Biosynthetic and catabolic pathways of H2S and persulfides.
Fig. 2: Recommended classification of biologically relevant sulfur species.
Fig. 3: Alkylation-based protein persulfide detection methods categorized based on similar measurement principles.
Fig. 4: Schematic summary of persulfidated target proteins included in this Review, with described functional consequences.

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Acknowledgements

The study was supported by the National Research, Development and Innovation Fund of the Ministry of Culture and Innovation under the National Laboratories Program, National Tumor Biology Laboratory (grant 2022-2.1.1-NL-2022-00010 to P.N.); the National Research, Development and Innovation Fund under the Hungarian Thematic Excellence Program (grant TKP2021-EGA-44 to P.N.); HUN-REN Hungarian Research Network (grant 1500207 to P.N.); Postdoctoral Excellence Fellowship (grant PD132082 to É.D.); NIH/NIA R01AG071512 (to B.D.P.), NIH/NIA R21AG073684 (to B.D.P.) and American Heart Association and Paul Allen Foundation Initiative in Brain Health and Cognitive Impairment (19PABH134580006 to B.D.P.) and Medical Research Council UK (MC_UU_00028/4 to M.P.M.) and a Wellcome Trust Investigator (award 220257/Z/20/Z to M.P.M). Support is acknowledged from Universidad de la República (EI_2020) and Programa de Alimentos y Salud Humana (IDB-R.O.U. 4950/OC-UR to R.R.). Additional funding was obtained from Programa de Desarrollo de Ciencias Básicas (to R.R.).

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Authors and Affiliations

  1. Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary

    Péter Nagy, Éva Dóka & Andrea Domán

  2. Department of Oncology, Semmelweis University, Budapest, Hungary

    Péter Nagy

  3. Department of Anatomy and Histology, HUN-REN–UVMB Laboratory of Redox Biology Research Group, University of Veterinary Medicine, Budapest, Hungary

    Péter Nagy

  4. Chemistry Coordinating Institute, University of Debrecen, Debrecen, Hungary

    Péter Nagy

  5. Department of Physiology, Pharmacology & Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Bindu D. Paul & Solomon H. Snyder

  6. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Bindu D. Paul & Solomon H. Snyder

  7. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Bindu D. Paul & Solomon H. Snyder

  8. Lieber Institute for Brain Development, Baltimore, MD, USA

    Bindu D. Paul

  9. Department of Internal Medicine, Division of Nephrology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    József Balla

  10. HUN-REN–UD Vascular Biology and Myocardium Pathophysiology Research Group, Hungarian Academy of Sciences, University of Debrecen, Debrecen, Hungary

    József Balla

  11. MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK

    Michael P. Murphy

  12. Department of Medicine, University of Cambridge, Cambridge, UK

    Michael P. Murphy

  13. Mātai Hāora—Centre for Redox Biology & Medicine, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand

    Christine Winterbourn

  14. Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay

    Rafael Radi

  15. Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay

    Rafael Radi

  16. Department of Pharmacology, UCLA School of Medicine, Beverly Hills, CA, USA

    Louis J. Ignarro

  17. Institute for Biochemistry and Molecular Biology I, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Helmut Sies

  18. Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany

    Helmut Sies

Authors
  1. Péter Nagy
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  2. Éva Dóka
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  3. Andrea Domán
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  4. Bindu D. Paul
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  5. József Balla
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Contributions

P.N. conceived the study. P.N., É.D., A.D., B.D.P., J.B., M.P.M., C.W., R.R., S.H.S., L.J.I. and H.S. contributed to the writing and editing of the manuscript.

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Correspondence to Péter Nagy.

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Nagy, P., Dóka, É., Domán, A. et al. Multifaceted roles for persulfide species in redox chemical biology. Nat Chem Biol (2026). https://doi.org/10.1038/s41589-026-02142-z

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