Targeting NFE2L1 signalling with small molecules to protect against Ferroptosis

Area of Science:

• Biochemistry
• Cell Biology
• Medicinal Chemistry

Background:

• Ferroptosis is a regulated cell death process linked to iron dysregulation, oxidative stress, and implicated in diseases like neurodegeneration and cancer.
• Nuclear factor erythroid 2-related factor 1 (NFE2L1) is a crucial transcription factor for maintaining cellular homeostasis and mitigating stress.
• Modulating ferroptosis presents a promising therapeutic avenue for various pathologies.

Purpose of the Study:

• To design and synthesize novel compounds that activate the NFE2L1 pathway.
• To evaluate the cytoprotective effects of these compounds against ferroptosis in cellular models.

Main Methods:

• Synthesis of a series of bis(dimethoxybenzylidene)oxocyclohexylsulfonamides and sulfamides.
• Assessment of NFE2L1 activation by the synthesized compounds.
• Testing compound efficacy in protecting SH-SY5Y neuroblastoma cells against ferroptosis-inducing agents (erastin, RSL3, FAC).

Main Results:

• Successfully designed and synthesized novel sulfonamide and sulfamide derivatives.
• Demonstrated robust activation of NFE2L1 by the synthesized compounds at low micromolar concentrations.
• Observed significant protection of human neuroblastoma cells against multiple ferroptosis inducers.

Conclusions:

• The developed compounds are potent NFE2L1 activators.
• These agents exhibit significant cytoprotective effects against ferroptosis.
• The findings highlight the therapeutic potential of NFE2L1-targeting agents for ferroptosis-related diseases.