Digoxin, an Overlooked Agonist of RORγ/RORγT

Area of Science:

• Immunology
• Molecular Biology
• Pharmacology

Background:

• Digoxin was initially identified as an inverse agonist of the Retinoid-related Orphan Receptor gamma (RORγT).
• High concentrations of digoxin exhibit cytotoxic effects, limiting its therapeutic potential.
• Structurally similar cardenolides were found to activate RORγ/RORγT-dependent transcription.

Purpose of the Study:

• To re-evaluate the effects of digoxin on RORγ/RORγT-dependent transcription at low, non-cytotoxic concentrations.
• To investigate digoxin's impact on Th17 cell differentiation and gene expression.
• To explore digoxin's potential as a RORγ/RORγT activator for therapeutic development.

Main Methods:

• Analysis of RORγ/RORγT-dependent transcription in HepG2 and Th17 cells treated with digoxin.
• Transcriptome analysis of Th17 cells cultured with digoxin.
• Assessment of Th17-specific gene expression, including IL17A/F, IL21, IL22, IL23R, CCR4, and CCR6.

Main Results:

• Digoxin induced RORγ/RORγT-dependent transcription in both HepG2 and Th17 cells.
• Low, non-cytotoxic concentrations of digoxin activated RORγ/RORγT.
• Digoxin treatment led to the induction of key Th17-specific genes in Th17 cells.

Conclusions:

• Digoxin acts as a potent RORγ/RORγT receptor activator at non-cytotoxic concentrations.
• The digoxin structure can serve as a basis for designing novel molecules for adoptive cell therapy (ACT).
• This research redefines digoxin's role in RORγ/RORγT modulation and its therapeutic implications.