Reviews:
Cell Stress, Vol. 9, No. 1, pp. 65 - 142; doi: 10.15698/cst2025.07.306
Nrf1 acts as a highly-conserved determinon for maintaining robust redox homeostasis in the eco-evo-devo process of life histories
1 The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Medical Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 400044, China. 2 School of Life and Health Sciences, Fuyao University of Science and Technology, No. 104 Wisdom Avenue, Nanyu Town, Minhou County High-Tech District, Fuzhou 350109, Fujian, China. 3 School of Basic Medicine, Guizhou Medical University, No. 6 Ankang Avenue, GUI ‘an New District, Guizhou 561113, China. 4 State Key Laboratory of Oil and Gas Reservoir Geology and Exploitation & Institute of Sedimentary Geology, Chengdu University of Technology, Chengdu 610059, China. 5 Key Laboratory of Deep-time Geography and Environment Reconstruction and Applications of Ministry of Natural Resources, Chengdu University of Technology, Chengdu 610059, China. 6 International Center for Sedimentary Geochemistry and Biogeochemistry Research, Chengdu University of Technology, Chengdu 610059, China. 7 Laboratory of Neuroscience, Institute of Cognitive Neuroscience and School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, England, United Kingdom. 8 Department of Experimental Embryology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzebiec, Poland. 9 African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43150, Morocco. 10 College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan 610044, China.
Keywords: Nrf1, Nrf2, homeostasis, determinon, regulon, topogenetics, redox stress, eco-evo-devo, redox code, stress-coping code, oncoprotist, ‘zero theory’, Reverse Central Dogma, Grand Redox-Unifying Theory (GRUT), and murburn concept.
Received originally: 16/09/2024 Received in revised form: 14/04/2025
Accepted: 05/05/2025
Published: 07/07/2025
Correspondence:
Yiguo Zhang, eaglezhang@fyust.edu.cn or yiguozhang@cqu.edu.cn
Conflict of interest statement: The authors declare no conflict of interest.
Please cite this article as: Yiguo Zhang, Xi Chen, Meng Wang, Yuping Zhu, Wei Shi, Chao Li, Zhengwen Zhang, Hiroaki Taniguchi and Ping Ao (2025). Nrf1 acts as a highly-conserved determinon for maintaining robust redox homeostasis in the eco-evo-devo process of life histories. Cell Stress 9: 65-142. doi: 10.15698/cst2025.07.306
Abstract
Differential and even opposing functions of two major antioxidant transcription factors Nrf1 and Nrf2 (encoded by Nfe2l1 and Nfe2l2, respectively) are determined by distinctions in their tempospatial positioning, topological repartitioning, proteolytic processing, and biochemical modification, as well as in their shared evolutionary origin. As a matter of fact, the allelopathic potentials of Nrf1 and Nrf2 (both resembling two entangled ‘Yin-Yang’ quanta that comply with a dialectic law of the unity of opposites) are fulfilled to coordinately control redox physiological homeostasis so as to be maintained within the presetting thresholds. By putative exponential curves of redox stress and intrinsic anti-redox capability, there is inferable to exist a set point at approaching zero with the ‘Golden Mean’ for the healthy survival (i.e., dubbed the ‘zero theory’). A bulk of the hitherto accumulating evidence demonstrates that the set point of redox homeostasis is dictated selectively by multi-hierarchical threshold settings, in which the living fossil-like Nrf1 acts as a robust indispensable determinon, whereas Nrf2 serves as a versatile chameleon-like master regulon, in governing the redox homeodynamic ranges. This is attributable to the facts that Nrf2 has exerted certain ‘double-edged sword’ effects on life process, whereas Nrf1 executes its essential physiobiological functions, along with unique pathophysiological phenotypes, by integrating its ‘three-in-one’ roles elicited as a specific triplet of direct sensor, transducer and effector within multi-hierarchical stress responsive signaling to redox metabolism and target gene reprogramming. Here, we also critically reviewed redox regulation of physio-pathological functions from the eco-evo-devo perspectives, through those coding rules (redox code, stress-coping code, and topogenetic code). The evolving concepts on stress and redox stress were also further revisited by scientific principles of physics and chemistry. Besides, several novel concepts such as oncoprotists, Reverse Central Dogma, and Grand Redox-Unifying Theory’ (GRUT) of life, together with diffusive reactive species (DRS)-based murburn concept integrating all stochastic electron-, proton- and/or moiety-transfer reactive and interactive processes (e.g., PCHEMS), are introduced in this interdisciplinary and synthetic review.
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Nrf1 acts as a highly-conserved determinon for maintaining robust redox homeostasis in the eco-evo-devo process of life histories by Zhang et al. is licensed under a Creative Commons Attribution 4.0 International License.
