OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer

Summary The deubiquitinase OTULIN removes methionine-1 (M1)-linked polyubiquitin chains to regulate TNF-mediated inflammation and cell death, but the physiological role of OTULIN outside the immune system is poorly understood. Here, we identify OTULIN as a liver tumour suppressor in mice. Hepatocyte-specific OTULIN deletion causes spontaneous steatohepatitis, extensive fibrosis, and pre-malignant tumours by eight weeks of age, which progresses to hepatocellular carcinoma by 7-12 months. OTULIN deficiency triggers apoptosis and inflammation in the liver, but surprisingly, steatohepatitis and pre-malignant growth is independent of TNFR1 signalling. Instead, the pathology in OTULIN-deficient livers is associated with increased mTOR activation, and mTOR inhibition with rapamycin reduces fibrosis and pre-malignant growth. This demonstrates that OTULIN is critical for maintaining liver homeostasis and preventing mTOR-driven liver disease.