NRF1 is upregulated by docosahexaenoic acid to ameliorate MASH through the inhibition of ER stress.

Despite the high prevalence of metabolic dysfunction-associated steatohepatitis (MASH), the number of effective therapeutic targets is limited due to a vague understanding of its intricate pathogenesis. In this study, we reported that the expression of nuclear factor erythroid-derived 2-related factor 1 (NRF1), an endoplasmic reticulum (ER) membrane-bound transcription factor that governs the expression of proteasome subunit genes, was significantly reduced in liver tissues from MAFLD patients and from mice fed a high-fat diet (HFD) for 20 weeks. Liver-specific overexpression of NRF1 in mice markedly ameliorated HFD-driven hepatic steatosis, liver injury and inflammation. Elevated NRF1 expression restored the function of the proteasome, facilitating the degradation of unfolded and nonfunctioning proteins, thereby mitigating ER stress and reducing oxidative stress. Moreover, docosahexaenoic acid (DHA) was found to increase NRF1 expression, contributing to the amelioration of MASH. Mechanistically, DHA inhibited the ubiquitination of NRF1 via the cytoplasmic E3 ligases FBW7 and HRD1 at the ER membrane, thereby preventing its degradation. Liver-specific knockdown of NRF1 abrogated the protective effect of DHA on HFD-driven MASH in mice. Together, our findings underscore the pivotal role of NRF1 in the DHA-mediated amelioration of MASH and suggest that NRF1 is a potential therapeutic target for MASH management.