Non-alcoholic steatohepatitis (NASH), characterised by presence of hepatic steatosis, lobular inflammation, and hepatocyte injury, can further progress to end-stage liver diseases and contributes to liver-related and all-cause mortality. Despite this increasing clinical epidemic, there are currently no approved pharmacotherapies for NASH and liver fibrosis. This is related to our limited understanding of the metabolic adaptations that occur within the liver during the development of NASH. To increase our understanding of changes in hepatic lipid metabolism in NASH, our group recently compared NASH pathology across eight common mouse strains fed a western-style diet, which was accompanied by detailed lipidomics profiling in the liver, and generation of bioinformatic prediction models of lipid metabolism pathways associated with susceptibility and resistance to NASH. Using this comprehensive lipidomics analysis, we identified various novel lipid metabolism pathways regulated with NASH, particularly phosphatidylserine (PS) synthesis as a novel signature of resistance to NASH. Increasing hepatic PS content through adeno-associated virus (AAV)-mediated overexpression of PSS1(Q353R), a gain of function mutant, in the livers of mice with NASH reduced lipid accumulation, and markers of liver injury and fibrogenesis, highlighting that increasing hepatic PS content may be a therapeutic strategy for prevention or reversal of NASH and liver fibrosis.