The hormetic dose-response mechanism: Nrf2 activation

Pharmacol Res. 2021 May:167:105526. doi: 10.1016/j.phrs.2021.105526. Epub 2021 Mar 2.


A generalized mechanism for hormetic dose responses is proposed that is based on the redox-activated transcription factor (TF), Nrf2, and its upregulation of an integrative system of endogenous anti-oxidant and anti-inflammatory adaptive responses. Nrf2 can be activated by numerous oxidative stressors (e.g., exercise, caloric restriction/intermittent fasting) and by exposures to synthetic, naturally occurring and endogenous chemicals, to non-ionizing (e.g., low-level light) and ionizing radiation, and to low-to-moderate stress from aging processes, among others. Nrf2 conducts crosstalk with other TFs to further integrate and enhance the effectiveness of adaptive metabolic strategies that produce acquired resilience. This adaptive mechanism of Nrf2 accounts for the generality and ubiquity of hormetic dose responses and supports the fundamental hormetic characteristic of protecting biological systems. At the same time, Nrf2 is highly evolutionarily conserved and quantitatively constrained in response (i.e., modest stimulatory response), further conserving biological resources and enhancing metabolic efficiencies. The notion that Nrf2 may serve as an hormetic mediator not only provides a regulatory-based evolutionary understanding of temporal acquired resilience and adaptive homeostasis but also causally integrates toxicological and pharmacological detoxification processes that are central to ecological and human risk assessments as well as to the development of drugs and therapeutics. These findings can also account for considerable inter-individual variation in susceptibility to toxic substances, the differential effectiveness of numerous therapeutic agents, and the variation in onset and severity of numerous age-related illnesses, such as type II diabetes.

Keywords: Acquired resilience; Adaptive response; Biphasic dose response; Hormesis; Nrf2; Redox sensor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Animals
  • Drug Discovery
  • Hormesis / drug effects
  • Humans
  • Light
  • Methylene Blue / pharmacology
  • Methylene Blue / therapeutic use
  • NF-E2-Related Factor 2 / metabolism*
  • Nervous System Diseases / drug therapy
  • Nervous System Diseases / metabolism
  • Oxidative Stress / drug effects
  • Phytochemicals / pharmacology
  • Phytochemicals / therapeutic use
  • Protective Agents / pharmacology
  • Protective Agents / therapeutic use
  • Radiation, Ionizing


  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Phytochemicals
  • Protective Agents
  • Methylene Blue