2. Academic Validation
  3. Sibiriline, a novel dual inhibitor of necroptosis and ferroptosis, prevents RIPK1 kinase activity and (phospho)lipid peroxidation as a potential therapeutic strategy

Sibiriline, a novel dual inhibitor of necroptosis and ferroptosis, prevents RIPK1 kinase activity and (phospho)lipid peroxidation as a potential therapeutic strategy

  • Cell Death Discov. 2025 Nov 28;11(1):552. doi: 10.1038/s41420-025-02852-8.
Claire Delehouzé 1 2,  Melodie Mallais 3,  Arnaud Comte 4,  Romain Lucas 1,  Blandine Baratte 2 5,  Sophie Bélal 1,  Axelle Autret 1,  Nathalie Py 6,  Rémy Steinschneider 6,  Lucie Adoux 7,  Benjamin Saintpierre 7,  Franck Letourneur 7,  Thomas Robert 2 5,  Céline Cougoule 8,  Caio Bomfim 8,  Rémi Planès 8,  David Péricat 8,  Jeannette Chloë Bulinski 2,  Marie-Thérèse Dimanche-Boitrel 9,  Peter Goekjian 10,  Etienne Meunier 8,  Morgane Rousselot 1,  Derek A Pratt 3,  Stéphane Bach 11 12
Affiliations

Affiliations

  • 1 SeaBeLife Biotech, Place Georges Teissier, 29680, Roscoff, France.
  • 2 Sorbonne Université, CNRS, Laboratoire de Biologie Intégrative des Modèles Marins, LBI2M, F-29680, Roscoff, France.
  • 3 Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON, Canada.
  • 4 Université de Lyon, CNRS UMR 5246, ICBMS, Chimiothèque, Université Claude Bernard Lyon 1, F-69622, Villeurbanne, France.
  • 5 Sorbonne Université, CNRS, Kinase Inhibitor Specialized Screening facility, KISSf, F-29680, Roscoff, France.
  • 6 Neuron Experts, Cité de la cosmétique, 2 rue Odette Jasse, 13015, Marseille, France.
  • 7 Plateforme GenomIC, Université de Paris, Institut Cochin, INSERM-CNRS, F-75014, Paris, France.
  • 8 Institut de Pharmacologie et Biologie Structurale (IPBS), Université de Toulouse, CNRS, Toulouse, France.
  • 9 France Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en santé, environnement et travail) - UMR_S 1085, F-35000, Rennes, France.
  • 10 Université de Lyon, CNRS UMR 5246, ICBMS, Laboratoire Chimie Organique 2-Glycosciences, Université Claude Bernard Lyon 1, F-69622, Villeurbanne, France.
  • 11 Sorbonne Université, CNRS, Laboratoire de Biologie Intégrative des Modèles Marins, LBI2M, F-29680, Roscoff, France. [email protected].
  • 12 Sorbonne Université, CNRS, Kinase Inhibitor Specialized Screening facility, KISSf, F-29680, Roscoff, France. [email protected].
PMID: 41315180 DOI: 10.1038/s41420-025-02852-8
Abstract

In the past two decades, various non-apoptotic pathways of regulated cell death have been identified; a small subset of these, including Necroptosis and Ferroptosis, manifests the phenotypic features of necrotic death. These two regulated necroses are being extensively studied because of their putative roles in severe acute and chronic pathologies. Moreover, as these regulated necrotic pathways are coactivated in a number of common pathologies, the development of multi-target directed ligands (that is, the use of a polypharmacological strategy) is a path-breaking avenue of research. In this study, we determined that the 7-azaindole derivative, sibiriline, inhibited both RIPK1-driven Necroptosis (induced by Tumor Necrosis Factor-α) and Ferroptosis (triggered by various classes of Ferroptosis inducers), with EC50s against each in the µM range. We next performed a combined large-scale transcriptomic study in order to determine the molecular mechanisms of action of sibiriline. We identified the stress response protein heme oxygenase-1 (HMOX1) as the main biomarker of Ferroptosis inhibition by sibiriline. We hypothesized that this compound reacts as an antioxidant to block ferroptosis; indeed, we found that sibiriline inhibits lipid peroxidation by trapping phospholipid-derived peroxyl radicals as a radical-trapping antioxidant (RTA). Taken together, these results show that sibiriline is a new dual inhibitor of Necroptosis and Ferroptosis cell death pathways; it works by inhibition of both RIPK1 kinase and (phospho)lipid peroxidation. We also demonstrate the in vitro efficacy of sibiriline to inhibit cell death in cell-based models of Parkinson's disease and cystic fibrosis. These findings shed light on the high therapeutic potency of RIPK1 inhibitors with RTA activity.

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