In a high-fat diet-induced NAFLD mouse model, researchers found that instability of the membrane protein NKAα1 and the resulting NKA dysfunction led to proteasome-mediated degradation of SIRT1 via ubiquitination, blockade of the autophagy signaling pathway, and exacerbation of hepatic steatosis, a process that could be inhibited by the deubiquitylating enzyme USP22 (68). Here, USP22 is linked to metabolic dysfunction-associated steatotic liver disease.