Grant: Canada Postdoctoral Research Award (CPRA) program

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the leading cause of chronic liver disease and liver transplant worldwide, affecting about one in three adults. MAFLD is strongly linked to obesity, diabetes, and cardiovascular disease, and is characterized by lipid accumulation and inflammation. MAFLD encompasses a spectrum of liver pathology ranging from simple steatosis to steatohepatitis (MASH), which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. Despite its prevalence and clinical burden, there are no approved treatments that reverse fibrotic progression in MASH. Autophagy is an essential cellular process responsible for degrading and recycling damaged organelles and lipids, to maintain liver homeostasis. Impaired autophagy contributes to maladaptive metabolic and inflammatory responses in MAFLD. This highlights an urgent need to investigate mechanisms that promote autophagy for the treatment of MAFLD. Autophagy inhibition in MAFLD is associated with increased Rubicon levels. Rubicon-mediated suppression of autophagy requires the interaction of Rubicon to a complex containing Rab7 and VPS34. Hence, interrupting Rubicon's interactions with Rab7 or VPS34 may restore autophagic function as a therapeutic strategy for MAFLD. In recent years, studies from our lab and others have demonstrated that Rubicon inhibition improves lipid metabolism and can reduce lipid deposition and cell death in MAFLD. We aim to assess whether targeted inhibition of Rubicon's RH and RUN domains disrupts interactions with Rab7 and VPS34, respectively. Inhibitory molecules of Rubicon will be evaluated in human hepatocytes and in mouse models of MAFLD. The proposed studies aim to validate novel treatments for future clinical translation and reduce the long-term health and economic burden of MAFLD.