Selective activation of cellular stress response pathways by fumaric acid esters

Area of Science:

• Cellular biology
• Molecular toxicology
• Biochemistry

Background:

• Cellular defense against oxidants and xenobiotics involves NRF2 and FOXO transcription factors.
• Activation of these pathways depends on protein thiol groups.
• Fumaric acid esters (FAEs) are thiol-reactive compounds.

Purpose of the Study:

• To investigate the activation of NRF2 and FOXO pathways by FAEs in human hepatoma cells.
• To determine the selectivity of FAEs towards NRF2 or FOXO signaling.

Main Methods:

• Treatment of cultured human hepatoma cells with various FAEs (dimethyl/diethyl, monomethyl/monoethyl fumarate).
• Assessment of glutathione levels and p38^MAPK activation.
• Analysis of NRF2 and FOXO target gene expression.

Main Results:

• All tested FAEs stabilized NRF2 and upregulated its target genes.
• Diester FAEs acutely depleted glutathione and activated p38^MAPK.
• No significant FOXO-dependent gene expression was observed following FAE treatment.

Conclusions:

• FAEs selectively activate the NRF2 signaling pathway.
• This selectivity suggests a targeted approach for modulating cellular stress responses.
• FAEs represent a promising class of compounds for NRF2 pathway activation.