2. Academic Validation
  3. Targeting NFE2L1 signalling with small molecules to protect against Ferroptosis

Targeting NFE2L1 signalling with small molecules to protect against Ferroptosis

  • Bioorg Med Chem Lett. 2025 Oct 3:130:130425. doi: 10.1016/j.bmcl.2025.130425.
Lucie Svobodová 1,  Jindřich Sedláček 2,  Zuzana Šmahelová 2,  Pavel Majer 3,  Aleš Machara 4,  Klára Grantz Šašková 5
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 16610 Prague, Czech Republic; Department of Organic Chemistry, Charles University, Hlavova 2030/8, Prague 2 12843, Czech Republic.
  • 2 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 16610 Prague, Czech Republic; Department of Genetics and Microbiology, Charles University and Research Center BIOCEV, Prumyslova 595, 25250 Vestec, Czech Republic.
  • 3 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 16610 Prague, Czech Republic.
  • 4 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 16610 Prague, Czech Republic. Electronic address: machara@uochb.cas.cz.
  • 5 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 16610 Prague, Czech Republic; Department of Genetics and Microbiology, Charles University and Research Center BIOCEV, Prumyslova 595, 25250 Vestec, Czech Republic. Electronic address: saskova2@natur.cuni.cz.
PMID: 41046920 DOI: 10.1016/j.bmcl.2025.130425
Abstract

Ferroptosis is a regulated form of cell death characterized by lipid peroxidation and excessive Reactive Oxygen Species (ROS) accumulation, which are driven primarily by iron dysregulation. It plays a critical role in neurodegeneration, Cancer, and ischaemia-reperfusion injury, making its modulation a promising therapeutic strategy. NFE2L1 (nuclear factor erythroid 2-related factor 1) is a key transcription factor in cellular homeostasis that mitigates oxidative and proteotoxic stress by regulating antioxidant, cytoprotective and proteostasis-related genes. In this study, we designed and synthesized a series of bis(dimethoxybenzylidene)oxocyclohexylsulfonamides and sulfamides that robustly activate NFE2L1. At low micromolar concentrations, these compounds protect human neuroblastoma SH-SY5Y cells from the ferroptosis-inducing agents erastin, RSL3, and ferric ammonium citrate (FAC)-induced oxidative cell death, demonstrating their potential as NFE2L1-targeting cytoprotective agents.

Keywords

Ferroptosis; NRF1 (NFE2L1); Oxytosis; Protective effect.

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