NRF2 Dysregulation and Therapeutic Insights Across Chronic Kidney Diseases

Abstract

Chronic kidney disease (CKD) remains a global health burden, with limited therapeutic options that effectively target the underlying pathophysiology. Nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of oxidative stress and inflammation, has garnered significant attention as a potential therapeutic target in CKD. Despite encouraging preclinical results, no NRF2-targeted agents have achieved clinical approval for CKD treatment. This review synthesizes emerging evidence showing substantial heterogeneity in NRF2 activity across CKD subtypes, influenced by disease etiology, CKD stage, and rate of disease progression. We elucidate the key therapeutic implications across diverse CKD etiologies and highlight that the therapeutic efficacy of NRF2 activation depends on precise modulation tailored to disease context. Although NRF2 overactivation and the need for stage-dependent modulation are increasingly recognized, this review further delineates the consequences of indiscriminate NRF2 activation, demonstrating that its effects diverge across CKD etiologies and cellular contexts. These insights support a nuanced, context-specific approach to NRF2-targeted strategies and provide a framework to guide future drug development in CKD.

Keywords: CKD; NRF2; dysregulation; etiology; therapeutic.

Figure 1

Oxidative/electrophilic stress and NRF2/KEAP1 signaling pathway. Under basal conditions (green box), Kelch-like ECH-associated protein 1 (KEAP1) serves as an adaptor to link nuclear factor erythroid 2-related factor 2 (NRF2) to the ubiquitin ligase cullin3-ring box 1 (Cul3-Rbx1) complex and leads to proteasomal degradation of NRF2. Upon exposure to reactive oxygen species (ROS) or electrophiles (red box), key cysteine residues within KEAP1 undergo covalent modification, impairing its ability to repress NRF2. This disruption permits NRF2 accumulation, followed by its translocation into the nucleus, where it heterodimerizes with small musculo-aponeutoric fibrosarcoma (sMAF) and binds to the antioxidant response element (ARE) to initiate the transcription of cytoprotective phase II detoxifying enzymes (NADPH-dehydrogenase quinone 1 (NQO1), heme oxygenase-1 (HO-1), glutamylcysteine synthetase (GCS)). As a delayed response to oxidative/electrophilic stress (yellow oval), glycogen synthase kinase-3β (GSK-3β) is activated and phosphorylates Fyn kinase. Following this, nuclear translocation of phosphorylated Fyn and KEAP1 phosphorylates NRF2 at Tyr568, which results in NRF2 nuclear exporting and degradation. Additionally, NRF2 degradation is facilitated by prothymosin α-mediated nuclear translocation of INRF2. Together, these cytoplasmic and nuclear degradation mechanisms tightly regulate NRF2 levels, ensuring rapid termination of its transcriptional activity once homeostasis is restored.