The global increase in obesity over the past few decades has caused a corresponding increase in NAFLD and its more severe form non-alcoholic steatohepatistis (NASH). Both NAFLD and NASH are associated with liver insulin resistance, non-alcoholic cirrhosis, and for the development of HCC. HCC is currently ranked as the fifth most common cancer worldwide and has a high mortality. It usually arises after years of liver disease and inflammation either due to chronic hepatitis B or C virus (HBV/HCV) infection, or alcoholic and non-alcoholic cirrhosis. SRSF3 is the smallest member of the SR protein family that function to promote RNA splicing by recruiting components of the spliceosome at constitutive and alternatively spliced exons. SRSF3 has also been ascribed a number of cellular functions including controlling cellular proliferation, as it is regulated during G1/S by the E2F transcription factor and controls the G2/M transition of immortal rat fibroblasts. Recent findings demonstrating that loss of SRSF3 triggers metabolic changes, hepatic fibrosis, and increased liver inflammation that are all features of early liver disease. The loss of expression of SRSF3 in the liver leads to chronic liver damage, fibrosis and eventually to hepatocellular carcinoma (HCC). In fact, SRSF3 is reduced in samples of human HCC as well as NAFLD, NASH and cirrhosis. SRSF3 protein levels are controlled in part by the conjugation of SRSF3 to an ubiquitin-like protein NEDD8 on Lys11, which results in its degradation by the proteasome in response to stress.