Alpha-1 Antitrypsin–Mediated Liver Disease: A Role for the NRF1–Proteasome Axis?

The ubiquitin–proteasome system (UPS) and autophagy are the two primary cellular pathways for degrading the Z mutant in Alpha 1-Antitrypsin Deficiency (AATD). These degradation pathways maintain hepatic cellular proteostasis in the context of AATD-mediated liver disease. Although alterations in proteasomal degradation have been demonstrated in AATD mouse models, the role of the UPS pathway in AATD-mediated liver disease remains poorly understood. Here, we show that the master regulator of proteostasis, nuclear factor erythroid 2-like 1 (NFE2L1 or NRF1), is activated in response to proteasome impairment caused by the Z variant, mediating proteasome recovery. Under basal conditions, this proteasome bounce-back response is sufficient to compensate for the impairment caused by Z variant expression. However, the NRF1–proteasome axis is downregulated in cirrhotic livers from AATD patients, suggesting that reduced NRF1 activity may contribute to the progression of AATD-associated liver disease. Our findings supported the involvement of the NRF1–proteasome axis in the hepatic proteotoxic response to Z-AAT and highlighted it as a potential therapeutic target to mitigate or prevent AATD-related liver injury.