NFE2L2 and Friedreich ataxia: However, unlike the expected activation of the NRF2-mediated antioxidant defense, the NRF2 signaling pathway is defective in FRDA patients and in preclinical models of FXN deficiency (Paupe et al., 2009; Shan et al., 2013; La Rosa et al., 2020a,b), thus further exacerbating the susceptibility to oxidative stress and its induced defects in the disease (Abeti et al., 2018; La Rosa et al., 2020c,d).