Screening natural products for the identification of NRF2 activity modulators

Aging is a complex biological process caused by the time-dependent loss of cellular homeodynamics and consequently of physiological organismal functions. This process is affected by both genetic and environmental (e.g., diet) factors, as well as by their constant interaction. The balanced functionality of (among others) cellular antioxidant, mitostatic and proteostatic modules is central to genome, mitochondrial and proteome stability. The antioxidant response system comprising the ubiquitously expressed NFE2-related transcription factor 2 (NRF2) and its redox-sensitive cytoplasmic inhibitor Kelch-like ECH-associated protein 1 (KEAP1) defends tissues against (among others) oxidative stress, thereby protecting against pathologies that relate to cellular biomolecules damage. We have shown the dose- and tissue-dependent activity of the NRF2/KEAP1 regulatory network during lifetime, as well as that NRF2 is part of a longevity promoting circuit that ensures functional wiring of proteostatic and mitostatic modules and consequently organismal survival during stress. We have also found a cytoprotective role of NRF2 in various age-related degenerative diseases, as well as that selected natural products can have a positive impact on cellular functionality, also via the activation of the NRF2 pathway, strongly supporting the notion that they can act as potential aging preventive agents and/or therapeutics for age-related disorders. Our rational and experimental platforms (both cell-free and cell-based, as well as at in vivo experimental models) for identifying modulators of NRF2 activity with anti-ageing and/or anti-age-related diseases (e.g., cancer, neurodegeneration, etc.) activity, along with some relevant recent findings, will be presented. Acknowledgments: We thank NKUA SARG (C.S. 19067) for support. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany