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    • Figure 1. 

      Cullin 3 and neddylation inhibitors exert dual metabolic effects in hepatocytes and adipocytes. (a) Structure of CRLs and neddylation processes involved in substrate recognition and degradation. (b) MLN4924 inhibits neddylation process, thereby increasing the stability of IRS to alleviate hepatic steatosis. (c) and (d) Hepatocyte or adipocyte-specific cullin 3 knockout induces persistent NRF2 activation, resulting in both beneficial and detrimental metabolic phenotypes. (e) Neddylation inhibitor TAS4464 stabilize and partial activate NRF2, promoting lipolysis and ameliorating obesity. (f) Adipose-specific cullin 3 heterozygous knockout induces intermittent NRF2 activation, leading to improved insulin sensitivity, obesity as well as hepatic steatosis. The graphic was created with BioRender.com (agreement number: KV29492SLA).