Mitochondria-targeted iridium-based photosensitizers enhancing photodynamic therapy effect by disturbing cellular redox balance.

University of Dundee Introduction to Special Issue on “Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases” Cuadrado, Antonio; Dinkova-Kostova, Albena T.; Mann, Giovanni E. Published in: Free Radical Biology and Medicine DOI: 10.1016/j.freeradbiomed.2022.12.100 Publication date: 2023 Licence: UK Government Non-Commercial Licence Document Version Publisher's PDF, also known as Version of record Link to publication in Discovery Research Portal Citation for published version (APA): Cuadrado, A., Dinkova-Kostova, A. T., & Mann, G. E. (2023). Introduction to Special Issue on “Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases”. Free Radical Biology and Medicine, 195, 258-260. https://doi.org/10.1016/j.freeradbiomed.2022.12.100 General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. May. 2026 Free Radical Biology and Medicine 195 (2023) 258–260 Contents lists available at ScienceDirect Free Radical Biology and Medicine journal homepage: www.elsevier.com/locate/freeradbiomed Introduction to Special Issue on “Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases” NRF2 (Nuclear factor erythroid 2-related factor 2) is a crucial tran scription factor for regulation of cellular homeostatic functions [1]. We will soon celebrate the thirtieth anniversary of its discovery [2]. Its mode of action involves heterodimerization with other bZip transcrip tion factors, of which the small MAF proteins F, G and K are the best characterized [3]. As illustrated in Fig. 1, the heterodimer activates the expression of genes that contain a specific enhancer, termed Antioxidant Response Element (ARE). These genes participate in protection against oxidative, inflammatory, metabolic or proteotoxic stress [4]. Given the tremendous impact of this protein in physiology and pathology, it is not surprising that it has attracted a great deal of attention by the biomed ical community. Moreover, contrary to most transcription factors, NRF2 is amenable to pharmacological activation by selectively inhibiting its degradation. The main repressor of NRF2 is the druggable E3 ligase adapter Kelch-likeECH-associated protein1 (KEAP1). Under unstressed conditions, KEAP1 targets NRF2 for Rbx1/Cullin 3-dependent ubiquiti nation and proteasomal degradation, but this repressor activity is blocked when specific cysteine residues in this protein are oxidized, or form adducts with electrophilic molecules. A much less explored mechanism of NRF2 repression is its glycogen synthase kinase (GSK-3)-mediated phosphorylation, which creates a phosphorylation-dependent site for interaction with the E3-ligase adapter β-transducin repeat-containing protein (β-TrCP). Binding of beta-TrCP to GSK-3-phosphorylated NRF2 leads to Rbx1/Cullin1-mediated ubiquitination and proteasomal degradation of NRF2. Therefore, KEAP1 and β-TrCP complement each other in NRF2 regulation under oxidative stress and cell signaling, respectively. A Special Issue published in Free Radical Biology & Medicine in 2016 highlighted some of the most important roles of NRF2 in physiology and pathology, as well as the regulation of its activity at several levels [5]. The current 2022 follow-up Special Issue is hosted by the European network CA20121 focused on “Bench to bedside transition for phar macological regulation of NRF2 in noncommunicable diseases (Ben BedPhar)” (https://e-services.cost.eu/action/CA20121). Its four-year mission is to extend and share basic, pharmacological, and clinical knowledge about NRF2, and to integrate it into the stream of social, clinical and economic sectors with capacity for translation into inno vative therapeutics for several non-communicable diseases. BenBedPhar currently includes more than 250 researchers from 33 countries. This Special Issue contains nineteen invited review and primary research articles, covering basic concepts and state of the art knowledge of the role of NRF2 in physiology and pathology as well as its pharma cological regulation. The paper by Kopacz et al. [6] draws attention to essential issues for newcomers to the field, highlighting overlooked facts https://doi.org/10.1016/j.freeradbiomed.2022.12.100 Available online 29 December 2022 0891-5849/Crown Copyright © 2022 Published by Elsevier Inc. All rights reserved. and clarifying potential misconceptions such as the unusual mobility of the NRF2 protein in SDS-PAGE, the need for the use of validated anti-NRF2 antibodies, the differences between the currently available Nrf2-knockout mice, the mechanistic interaction of the NRF2/KEAP1 pair, etc. A new and very promising tool for the study of NRF2 activation at the single cell level is reported in the experimental paper by Kitamura et al. [7], which describes a Neh2-Cre:tdTomato reporter mouse. Current knowledge about the role of NRF2 in mitochondrial function and structure is reviewed in Ref. [8], with a focus on energy production, reactive oxygen species generation, calcium signaling, and cell death. Moreover, in the context of energy metabolism, a very exciting link between NRF2 and AMP-activated kinase (AMPK) is described by Pet souki et al. [9]. Regarding regulation of NRF2 by kinase cascades, another experimental paper is provided by Ishii et al. [10], which pro poses that Cav1 serves as a hub for the control of H2O2-mediated phosphorylation of NRF2 by p38/nSMase2/ceramide signaling. Boor man et al. [11] gather current evidence about a role of NRF2 in regu lation the neurogenic niches from early neural lineage specification and neural stem cell regulation to neuronal fate commitment and differentiation. Accumulating evidence indicates a link between NRF2 and many chronic diseases. Moreover, pharmacological inhibition of KEAP1, leading to NRF2 activation, is providing proof of concept that NRF2 activation might be beneficial in many non-communicable diseases. Thus, Kopàz et al. [12] report that NRF2 deficiency leads to impairment of the gastrointestinal system in young females in connection with ERβ signaling. Current knowledge about the participation of NRF2 in phys iology, pathophysiology and disease of the thyroid gland is analyzed by Chartoumpekis et al. [13]. A comprehensive review of the role of NRF2 in protection against non-alcoholic steatohepatitis and its potential use as a pharmacological target is provided in Batish et al. [14]. Another experimental paper by Gou et al. [15] shows that loss of NRF2 activity in periodontal ligament cells during bacterial and hypoxia events is tightly linked with periodontitis. In the context of neurodegenerative disease, the experimental paper by Anandhan et al. [16] reports that α-syn overexpression and NRF2 suppression lead to enhanced neuronal fer roptotic cell death in a model of Parkinson’s disease. Manda et al. [17] discuss the involvement of NRF2 in rheumatoid arthritis according to findings from human transcriptomics and mouse models, and also consider a potential drawback of NRF2-based therapy due to increasing anti-rheumatic drugs efflux. The dark side of NRF2 hyperactivation is most evident in cancer because NRF2 makes tumor cells resistant to chemo-, immuno-, and radiotherapy, highlighting the need for NRF2 inhibitors. The review by Srivastava et al. [18] discusses novel A. Cuadrado et al. Free Radical Biology and Medicine 195 (2023) 258–260 transcriptional repressor of a subset of NRF2-target genes. The longer-term objective of Free Radical Biology & Medicine is to provide readers with informed updates of this important research field every 4 years. Acknowledgements The authors acknowledge the support by European COST Action CA20121: Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases (BenBedPhar). Webpage: https://benbedphar.org/about-benbedphar/. References [1] A. Cuadrado, A.I. Rojo, G. Wells, J.D. Hayes, S.P. Cousin, W.L. Rumsey, O. C. Attucks, S. Franklin, A.L. Levonen, T.W. Kensler, A.T. Dinkova-Kostova, Ther apeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases, Nat. Rev. Drug Discov. 18 (2019) 295–317. [2] P. Moi, K. Chan, I. Asunis, A. Cao, Y.W. Kan, Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region, Proc. Natl. Acad. Sci. U. S. A. 91 (1994) 9926–9930. [3] T. Sengoku, M. Shiina, K. Suzuki, K. Hamada, K. Sato, A. Uchiyama, S. Kobayashi, A. Oguni, H. Itaya, K. Kasahara, H. Moriwaki, C. Watanabe, T. Honma, C. Okada, S. Baba, T. Ohta, H. Motohashi, M. Yamamoto, K. Ogata, Structural basis of tran scription regulation by CNC family transcription factor, Nrf2, Nucleic Acids Res. 50 (2022) 12543–12557. [4] A. Cuadrado, G. Manda, A. Hassan, M.J. Alcaraz, C. Barbas, A. Daiber, P. Ghezzi, R. Leon, M.G. Lopez, B. Oliva, M. Pajares, A.I. Rojo, N. Robledinos-Anton, A. M. Valverde, E. Guney, H. Schmidt, Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach, Pharmacol. Rev. 70 (2018) 348–383. [5] G.E. Mann, H.J. Forman, Introduction to special issue on ’Nrf2 regulated redox signaling and metabolism in physiology and medicine, Free Radic. Biol. Med. 88 (2015) 91–92. [6] A. Kopacz, A.I. Rojo, C. Patibandla, D. Lastra-Martinez, A. Piechota-Polanczyk, D. Kloska, A. Jozkowicz, C. Sutherland, A. Cuadrado, A. Grochot-Przeczek, Over looked and valuable facts to know in the NRF2/KEAP1 field, Free Radic. Biol. Med. 192 (2022) 37–49. [7] H. Kitamura, T. Oishi, S. Murakami, T. Yamada-Kato, I. Okunishi, M. Yamamoto, Y. Katori, H. Motohashi, Establishment of Neh2-Cre:tdTomato reporter mouse for monitoring the exposure history to electrophilic stress, Free Radic. Biol. Med. 193 (2022) 610–619. [8] N. Esteras, A.Y. Abramov, Nrf2 as a regulator of mitochondrial function: energy metabolism and beyond, Free Radic. Biol. Med. 189 (2022) 136–153. [9] E. Petsouki, S.N.S. Cabrera, E.H. Heiss, AMPK and NRF2: interactive players in the same team for cellular homeostasis? Free Radic. Biol. Med. 190 (2022) 75–93. [10] T. Ishii, E. Warabi, G.E. Mann, Mechanisms underlying Nrf2 nuclear translocation by non-lethal levels of hydrogen peroxide: p38 MAPK-dependent neutral sphin gomyelinase2 membrane trafficking and ceramide/PKCzeta/CK2 signaling, Free Radic. Biol. Med. 191 (2022) 191–202. [11] E. Boorman, R. Killick, D. Aarsland, P. Zunszain, G.E. Mann, NRF2: an emerging role in neural stem cell regulation and neurogenesis, Free Radic. Biol. Med. 193 (2022) 437–446. [12] A. Kopacz, D. Kloska, J. Fichna, D. Klimczyk, M. Kopec, A. Jozkowicz, A. PiechotaPolanczyk, The lack of transcriptionally active Nrf2 triggers colon dysfunction in female mice - The role of estrogens, Free Radic. Biol. Med. 192 (2022) 141–151. [13] D.V. Chartoumpekis, P.G. Ziros, I.G. Habeos, G.P. Sykiotis, Emerging roles of Keap1/Nrf2 signaling in the thyroid gland and perspectives for bench-to-bedside translation, Free Radic. Biol. Med. 190 (2022) 276–283. [14] B. Bathish, H. Robertson, J.F. Dillon, A.T. Dinkova-Kostova, J.D. Hayes, Nonalco holic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2, Free Radic. Biol. Med. 188 (2022) 221–261. [15] H. Gou, X. Chen, X. Zhu, L. Li, L. Hou, Y. Zhou, Y. Xu, Sequestered SQSTM1/p62 crosstalk with Keap1/NRF2 axis in hPDLCs promotes oxidative stress injury induced by periodontitis, Free Radic. Biol. Med. 190 (2022) 62–74. [16] A. A, C. W, N. N, M. L, D. M, D.D. Zhang, alpha-Syn overexpression, NRF2 sup pression, and enhanced ferroptosis create a vicious cycle of neuronal loss in Par kinson’s disease, Free Radic. Biol. Med. 192 (2022) 130–140. [17] G. Manda, E. Milanesi, S. Genc, C.M. Niculite, I.V. Neagoe, B. Tastan, E. M. Dragnea, A. Cuadrado, Pros and cons of NRF2 activation as adjunctive therapy in rheumatoid arthritis, Free Radic. Biol. Med. 190 (2022) 179–201. [18] R. Srivastava, R. Fernandez-Gines, J.A. Encinar, A. Cuadrado, G. Wells, The current status and future prospects for therapeutic targeting of KEAP1-NRF2 and betaTrCP-NRF2 interactions in cancer chemoresistance, Free Radic. Biol. Med. 192 (2022) 246–260. [19] M.T. Bayo Jimenez, K. Frenis, O. Hahad, S. Steven, G. Cohen, A. Cuadrado, T. Munzel, A. Daiber, Protective actions of nuclear factor erythroid 2-related factor 2 (NRF2) and downstream pathways against environmental stressors, Free Radic. Biol. Med. 187 (2022) 72–91. Fig. 1. Regulation of NRF2 by KEAP1. Dimeric KEAP1 binds to the ‘DLG’ and ‘ETGE’ motifs of NRF2 and targets the transcription factor for ubiquitination and proteasomal degradation. Electrophiles and reactive oxygen species (ROS) modify specific cysteines in KEAP1, disabling its substrate adapter function without disrupting the KEAP1–NRF2 interaction. By contrast, KEAP1–NRF2 protein-protein interaction (PPI) inhibitors disrupt the DLG–KEAP1 interaction preferentially to the ETGE–KEAP1 interaction. Consequently, newlysynthesized NRF2 accumulates, translocates to the nucleus, forms a hetero dimer with a small MAF transcription factor, and the heterodimer activates the transcription of genes that contain antioxidant response elements (AREs) in their regulatory regions. SH = reduced cysteine; S* = modified cysteine. approaches to inhibit NRF2 by enhancing with molecular glues its interaction with the main repressors KEAP1 and β-TrCP. Three studies deal with significant challenges to mankind caused by environmental factors. Thus, Bayo-Jiménez et al. [19] discuss the impact of noise and air pollution on the circadian rhythm and the interactions of NRF2 and its target heme oxygense-1 (HO-1) with the circadian clock. Kahremany et al. [20] comment on the damage to skin by ultraviolet radiation and how NRF2 activators might protect against cutaneous photodamage and photodermatoses. In a similar context, Wakamori et al. [21] provide experimental evidence that pharmacological activa tion of NRF2 protects against radiation-induced oral mucositis via antioxidation and keratin layer thickening. Most of these articles address the pharmacological regulation of NRF2 with a wide armamentarium of small molecule activators. More over, we also present three novel NRF2 activators. The paper by Yao et al. [22] uses panaxatriol saponin to ameliorate myocardial infarction-induced cardiac fibrosis in a NRF2/KEAP1 dependent manner. Yilmaz et al. [23] report that cycloastragenol activates telo merase in a NRF2-dependent manner, suggesting an anti-ageing effect. Finally, Moreno et al. [24], show that a biotinylated derivative of an acetylenic tricyclic bis(cyanoenone), but not its parent compound, ex hibits bifunctional effects, activating NRF2 and inhibiting BACH1, a 259 A. Cuadrado et al. Free Radical Biology and Medicine 195 (2023) 258–260 Faculty of Medicine, Autonomous University of Madrid, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain [20] S. Kahremany, L. Hofmann, A. Gruzman, A.T. Dinkova-Kostova, G. Cohen, NRF2 in dermatological disorders: pharmacological activation for protection against cuta neous photodamage and photodermatosis, Free Radic. Biol. Med. 188 (2022) 262–276. [21] S. Wakamori, K. Taguchi, Y. Nakayama, A. Ohkoshi, M.B. Sporn, T. Ogawa, Y. Katori, M. Yamamoto, Nrf2 protects against radiation-induced oral mucositis via antioxidation and keratin layer thickening, Free Radic. Biol. Med. 188 (2022) 206–220. [22] H. Yao, Q. He, C. Huang, S. Wei, Y. Gong, X. Li, W. Liu, Z. Xu, H. Wu, C. Zheng, Y. Gao, Panaxatriol saponin ameliorates myocardial infarction-induced cardiac fibrosis by targeting Keap1/Nrf2 to regulate oxidative stress and inhibit cardiacfibroblast activation and proliferation, Free Radic. Biol. Med. 190 (2022) 264–275. [23] S. Yilmaz, E. Bedir, P. Ballar Kirmizibayrak, The role of cycloastragenol at the intersection of NRF2/ARE, telomerase, and proteasome activity, Free Radic. Biol. Med. 188 (2022) 105–116. [24] R. Moreno, L. Casares, M. Higgins, K.X. Ali, T. Honda, C. Wiel, V.I. Sayin, A. T. Dinkova-Kostova, L. de la Vega, Biotinylation of an acetylenic tricyclic bis (cyanoenone) lowers its potency as an NRF2 activator while creating a novel ac tivity against BACH1, Free Radic. Biol. Med. 191 (2022) 203–211. Albena T. Dinkova-Kostova Jacqui Wood Cancer Centre, Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, Scotland, United Kingdom E-mail address: a.dinkovakostova@dundee.ac.uk. Giovanni E. Mann British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life & Health Sciences, King’s College London, 150 Stamford Street, London, SE19NH, UK E-mail address: giovanni.mann@kcl.ac.uk. Antonio Cuadrado* Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, * Corresponding author. E-mail address: antonio.cuadrado@uam.es (A. Cuadrado). 260