Non-Electrophilic Activation of NRF2 in Neurological Disorders: Therapeutic Promise of Non-Pharmacological Strategies

Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2) serves as a master transcriptional regulator of cellular antioxidant responses through orchestration of cytoprotective gene expression, establishing its significance as a therapeutic target in cerebral pathophysiology. Classical electrophilic NRF2 activators, despite potent activation potential, exhibit paradoxically reduced therapeutic efficacy relative to single antioxidants, attributable to concurrent oxidative stress generation, glutathione depletion, mitochondrial impairment, and systemic toxicity. Although emerging non-electrophilic pharmacological activators offer therapeutic potential, their utility remains limited by bioavailability and suboptimal potency, underscoring the imperative for innovative therapeutic strategies to harness this cytoprotective pathway. Non-pharmacological interventions, including neuromodulation, physical exercise, and lifestyle modifications, activate NRF2 through non-canonical, non-electrophilic pathways involving protein-protein interaction inhibition, KEAP1 degradation, post-translational and transcriptional modulation, and protein stabilization, though mechanistic characterization remains incomplete. Such interventions utilize multi-mechanistic approaches that synergistically integrate multiple non-electrophilic NRF2 pathways or judiciously combine electrophilic and non-electrophilic mechanisms while mitigating electrophile-induced toxicity. This strategy confers neuroprotective effects without the contraindications characteristic of classical electrophilic activators. This review comprehensively examines the mechanistic underpinnings of non-pharmacological NRF2 modulation, highlighting non-electrophilic activation pathways that bypass the limitations inherent to electrophilic activators. The evidence presented herein positions non-pharmacological interventions as viable therapeutic approaches for achieving non-electrophilic NRF2 activation in the treatment of cerebrovascular and neurodegenerative pathologies.

Keywords: NRF2; electrophilic; neurological disorders; neuromodulation; non-electrophilic; non-pharmacological intervention.

Figure 1

Paradoxical consequences of electrophilic NRF2 activation. Although NRF2 coordinates the transcription of hundreds of antioxidant and cytoprotective genes, single antioxidant agents can, paradoxically, outperform classical electrophilic NRF2 inducers in therapeutic settings. This diminished efficacy arises from liabilities inherent to electrophilic compounds, including (1) depletion of intracellular glutathione, (2) exacerbation of protein oxidation, (3) amplification of reactive oxygen species, (4) disruption of mitochondrial bioenergetics, and (5) off-target organ toxicity—most notably hepatic, cardiac, and renal injury. These contraindications highlight the imperative to investigate non-electrophilic NRF2 activators. (Created with BioRender.com).

Figure 2

Mechanistic spectrum of NRF2 activation. (A) NRF2 can be activated through six principal routes: (1) non-specific electrophile/ROS generation, (2) disruption of the NRF2–KEAP1 protein–protein interface, (3) autophagy-driven KEAP1 degradation, (4) direct stabilization of NRF2, (5) post-transcriptional regulation, and (6) post-translational modification. Despite the fact that only pathway 1 is electrophilic, >90% of currently available small-molecule activators exploit electrophilic chemistry. (B) Non-pharmacological NRF2 inducers display a markedly different mechanistic distribution: they are enriched for non-electrophilic pathways and often engage multiple mechanisms concurrently. Of the twelve non-pharmacological interventions assessed in this review—excluding the two whose mechanisms have yet to be elucidated—only therapeutic hypothermia operates purely through an electrophilic mechanism. The four other interventions that exhibit some degree of electrophilicity do so in conjunction with additional, non-electrophilic pathways, highlighting their mechanistic divergence from conventional electrophile-based activators.

Figure 3

Non-pharmacological modalities predominantly engage multiple NRF2-activating pathways. NRF2 can be induced via: (i) non-specific electrophile/ROS generation, (ii) disruption of the NRF2–KEAP1 protein–protein interaction, (iii) autophagy-mediated KEAP1 degradation, (iv) direct modulation of NRF2 protein stability, and (v) post-transcriptional/post-translational modifications. Except for a single intervention, therapeutic hypothermia, every non-pharmacological strategy with defined mechanisms employs more than one of these routes, most frequently pairing post-translational modification with either protein-stability regulation or limited electrophile production. This combinatorial activation elevates both NRF2 abundance and transcriptional competence while minimizing the liabilities of purely electrophilic agents and circumventing the efficacy limitations reported for current single-mechanism, non-electrophilic compounds. (Created with BioRender.com) (abbreviations: α7nACHr: alpha7 nicotinic acetylcholine receptor; Akt: protein kinase B; AMPK: AMP-activated protein kinase; BDNF: brain-derived neurotrophic factor; CB2r: Cannabinoid receptor 2; ERK: extracellular signal-regulated kinase; GSK-3β: glycogen synthase kinase 3 beta; miR-144: microRNA-144; p38 MAPK: p38 mitogen-activated protein kinase; p62; ROS: reactive oxygen species; SIRT1: sirtuin 1; SIRT3: sirtuin 3; STAT3: signal transducer and activator of transcription 3; TOPK: T-LAK cell-originated protein kinase).

Figure 4

Cell-type-dependent NRF2 engagement. Neurons, oligodendrocytes, astrocytes, microglia, and vascular cells possess distinct NRF2 regulatory baselines that reflect their intrinsic oxidative stress susceptibility. Consequently, the optimal route of NRF2 induction varies across cell types and, by extension, across neurological diseases dominated by those cells. Although direct cell-specific data for non-pharmacological interventions are not yet available, the signaling pathways they recruit provide a rationale for therapeutic matching. Modalities such as physical exercise and DR activation, which primarily engage neuronal and oligodendroglial NRF2 signaling, may be preferable for disorders characterized by parenchymal injury. In contrast, interventions that robustly influence vascular NRF2 networks, e.g., electroacupuncture or electroconvulsive stimulation, may prove more advantageous in pathologies driven by cerebrovascular dysfunction. (Created with BioRender.com).