*5.1. NRF2–KEAP1 Signaling Pathway*

Several groups have independently shown beneficial associations and e ffects of the NRF2 system as a key regulator of anti-oxidative enzymes in CKD, and promote NRF2 as a multiorgan protector.

Concluding the findings discussed above, treatment of the repressed NRF2 system in CKD can improve oxidative stress and mitochondrial function [125,149], inflammation [27,123,149], as well as premature ageing [122], in particular EVA [120,121].

NRF2-inducing treatment options include nutritional components, exercise [150], and pharmaceutical compounds targeting NRF2 or inhibiting the binding of NRF2 to KEAP1 [116]. Although the above-mentioned beneficial effects of NRF2 have drawn interest to this molecular "health promoter", potential caveats should be acknowledged. Firstly, NRF2 has dual roles in its association with carcinogenesis, as well as cancer progression and therapy. Thus, NRF2 activation in normal cells can prevent cancer initiation [151]. In contrast, prolonged NRF2 activation is involved in cancer promotion, progression, and treatment resistance [151]. Consequently, each NRF2-based approach must carefully investigate oncogenic risk as a potential side e ffect. Secondly, despite promising initial results, previous treatment approaches for patients with DKD using the NRF2 agonist bardoxolone have been stopped

due to an excess of heart failure hospitalizations among those assigned to bardoxolone [7]. However, because patients with risk factors for heart failure could be identified and excluded, bardoxolone is currently being re-investigated in di fferent clinical trials comprising patients with CKD and underlying pathologies [116]. When patients in these studies are carefully selected, the NRF2 agonist might have beneficial e ffects on several hallmarks of the uremic phenotype, such as inflammation, oxidative stress, as well as on premature ageing. Thus, NRF2 is currently a promising and the clinically most advanced signaling pathway for the treatment of both inflammation and premature ageing in CKD. It should be kept in mind that it is also possible to target NRF2 by nutraceuticals, such as sulforaphane [7].
