Nrf2/UBE3B protects against acute lung injury by inhibiting ferritinophagy through the ubiquitination of NCOA4

Iron overload and ferroptosis are associated with intestinal ischemia and reperfusion (II/R)-induced acute lung injury (ALI). However, the mechanisms underlying the regulation of iron homeostasis remain unclear. Nrf2 regulates cellular iron homeostasis; however, its impact on ALI pathology and its underlying mechanism of action requires further investigation. Ubiquitin ligase E3B (UBE3B) plays a critical role in the proteasome pathway, which is essential for protein turnover and ubiquitin-mediated signaling. A recent study found that UBE3B plays a role in oxidative stress; however, it remains unknown whether its role is related to Nrf2. Furthermore, the exact role of UBE3B in ALI and its underlying mechanism remain largely uncharacterized. In the present study, immunohistochemical analysis of UBE3B expression in type II alveolar epithelial cells (AECII) was conducted and its expression was found to be increased in II/R-ALI. Western blot analysis indicated that UBE3B hyperactivation may alleviate oxidative stress, thereby protecting against ALI. Moreover, UBE3B was involved in iron metabolism dysfunction and ferroptosis. UBE3B deficiency enhanced the process of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and increased ferrous ion content, whereas overexpression of UBE3B reversed the harmful effects of Nrf2 knockdown on AECⅡ, which may promote AECⅡ ferroptosis. This study highlights the role of the Nrf2/UBE3B/NCOA4 axis in AECⅡ ferroptosis and II/R-ALI pathogenesis, suggesting that Nrf2 activation may be a promising strategy for ALI treatment.