The hormetic dose-response mechanism: Nrf2 activation

Area of Science:

• Toxicology
• Cellular Biology
• Genetics

Background:

• Hormetic dose responses, characterized by a biphasic effect where low doses stimulate and high doses inhibit, are widely observed but lack a generalized mechanistic explanation.
• The transcription factor Nrf2 (Nuclear factor erythroid 2-related factor 2) is a key regulator of cellular defense against oxidative stress.

Purpose of the Study:

• To propose a generalized mechanism for hormetic dose responses centered on the Nrf2 pathway.
• To elucidate how Nrf2 integrates various adaptive responses and contributes to acquired resilience.

Main Methods:

• The study proposes a mechanism based on the known functions and regulation of Nrf2.
• It integrates existing knowledge of Nrf2's role in response to diverse stressors and its interactions with other transcription factors.

Main Results:

• Nrf2 activation by various stressors (oxidative, chemical, radiation, aging) upregulates endogenous antioxidant and anti-inflammatory responses.
• Nrf2 crosstalks with other transcription factors, enhancing adaptive metabolic strategies and acquired resilience.
• The Nrf2 pathway's evolutionary conservation and constrained response explain the ubiquity and protective nature of hormesis.

Conclusions:

• Nrf2 serves as a central mediator of hormetic dose responses, providing an evolutionary and regulatory framework for adaptive homeostasis.
• This mechanism integrates toxicological and pharmacological detoxification, impacting risk assessment and therapeutic development.
• The Nrf2 pathway explains inter-individual variations in toxicity susceptibility, drug efficacy, and age-related disease onset.