Nfe2l3 (also known as Nrf3) belongs to the Cap'n'collar (Cnc) family of proteins, along with Nfe2l1 and Nfe2l2, which regulate several physiological and pathophysiological processes, including cellular response to oxidative stress (Sykiotis and Bohmann, 2010; Liu et al., 2019). Nfe2l3 itself is involved in antioxidant response, lipid metabolism, proliferation, and oligodendrocyte differentiation (Sykiotis and Bohmann, 2010; Liu et al., 2019; Sankaranarayanan and Jaiswal, 2004; Waku et al., 2021; Chowdhury et al., 2017; Zilkha-Falb et al., 2017). Multiple factors upstream and downstream of Nfe2l3 also have been identified (Liu et al., 2019; Chowdhury et al., 2017; Wang et al., 2019). Nfe2l3 knockout (KO) mice develop without overt abnormalities, presumably due to redundancy with Nfe2l1 or Nfe2l2 members of the same protein family (Derjuga et al., 2004). However, Nfe2l3 KO mice challenged with pulmonary injury lose weight (Chevillard et al., 2010), and when challenged with carcinogens produce lymphoblasts (Chevillard et al., 2011). In the adult central nervous system (CNS), based on single cell transcriptomics, Nfe2l3 is expressed primarily in oligodendrocytes, but not expressed meaningfully in neurons (Saunders et al., 2018). Nevertheless, at least embryonically and neonatally, Nfe2l3 was associated with the development of cortical layer 5 pyramidal near-projecting and corticothalamic projection neurons, respectively (Munz et al., 2023; Galazo et al., 2016), in which its expression declined during maturation and was silenced by adult age (Clark et al., 2020). Because in the CNS neuronal intrinsic axon growth capacity declines during developmental maturation (Goldberg et al., 2002; Moore et al., 2009), it is possible that Nfe2l3, whose expression declines during maturation in subsets of cortical projection neurons, may play a role in developmental axon growth of certain types of neurons. Although Nfe2l3 KO mice appear to develop normally (which could be due to compensatory redundancy with Nfe2l1 and Nfe2l2), Nfe2l3 KO mice exhibit phenotypes when challenged (Chevillard et al., 2010; Chevillard et al., 2011). Thus, we hypothesized that the Nfe2l3 may exhibit axon growth phenotype when challenged by injury. Because oxidative stress is one of the earliest pathological intracellular events in RGCs after axonal optic nerve crush (ONC) injury (Kanamori et al., 2010), whereas Nfe2l3 is associated with antioxidant response (Sykiotis and Bohmann, 2010; Liu et al., 2019; Sankaranarayanan and Jaiswal, 2004), we selected ONC as a challenge for investigating Nfe2l3's potential neuronal functions in vivo. First, we asked whether Nfe2l3 expression is associated with development of other cortical and retinal ganglion cell (RGC) CNS projection neurons. Then, we tested whether expressing Nfe2l3 in RGCs would elicit neuroprotection and/or promote axon regeneration after challenge by ONC injury, and compared the effects to targeting of prominent regulators of long-distance axon regeneration, Pten and Klf9 (Park et al., 2008; Rheaume et al., 2023; Apara et al., 2017; Trakhtenberg et al., 2018). Finally, we characterized gene network associated with Nfe2l3 in neonatal RGCs (before its expression declines during maturation), which provided insights into the potential molecular mechanisms of Nfe2l3 functions in neurons.