Fat accumulation, lipogenesis and glycolysis are key contributors to hepatocyte metabolic reprogramming and the pathogenesis of non-alcoholic liver fatty liver disease (NAFLD). The molecular mechanisms affected by steatosis and inflammation in the obese state remain unknown. Here we report that obesity leads to dysregulated expression of protein-tyrosine phosphatases in human livers. Protein Tyrosine Phosphatase Receptor Kappa (PTPRK) levels were increased in hepatocytes by steatosis and inflammation in humans and mice and positively correlates with PPARy-induced lipogenic PTPRK- PPARyupregulation is dependent upon Notch activation. PTPRK knockout male and female mice have reduced fat accumulation and liver steatosis after twelve weeks of obesogenic diet feeding. lmmunoblot and qPCR analyses of liver samples showed diminished levels of PPARy, nutrient-sensitive transcription factors (SREP1 and ChREBP), and lipogenic enzymes (FASN and ACC) in obese PTPRK knockout mice compared to controls. Phosphoproteomics analysis in isolated hepatocytes identified specific phosphotyrosine residues in fructose-1,6 bisphosphatase/FBP1 and glycolysis regulation as a target of PTPRK. Computational modeling and in vitro analysis confirmed FBP1-PTPRK interaction and PTPRK-mediated pFBP1 (Y265) dephosphorylation. Metabolomic analysis showed lower levels of dihydroxyacetone-phosphate and gIyceraIdehyde-3-phosphate, while pyruvate, a-ketoglutarate and ribose-5-phosphate were increased in livers from PTPRK knockout mice compared with controls. These metabolic changes in glycolysis/gluconeogenesis, TCA cycle and pentose phosphate pathway revealed metabolic reprogramming in hepatocytes mediated by PTPRK. Adenoviral-mediated overexpression of PTPRK increased glycolytic capacity in mouse hepatocytes. RNA-Seq analysis in human samples demonstrated positive correlations between PTPRK expression levels and glycolytic and lipogenic genes in NAFLD-associated hepatocellular carcinoma. Moreover, glycolytic-dependent hepatoma cell lines showed reduced colony-forming ability after PTPRK silencing in vitro and PTPRK knockout mice developed smaller tumours after diethylnitrosamine-induced hepatocarcinogenesis in vivo. Computational modelling identified potential PTPRK inhibitors, which selectively reduced PTPRK activity and decreased glycolytic rates in hepatoma cell lines and prevented PPARy overexpression in primary hepatocytes. Administration of these inhibitors to high-fat fed mice resulted in reductions in body weight, fat mass, glycemia, and liver fat content, underscoring their potential for managing obesity-associated liver and metabolic dysfunctions. In conclusion, our study defines an unprecedented mechanism for the development of NAFLD, revealing a key role of PTPRK on hepatic lipid metabolism, gluconeogenesis/glycolysis regulation and liver tumour development. We propose PTPRK as a potential target for metabolic liver dysfunction, and the identified inhibitors may represent promising candidates for therapy in obesity-associated liver diseases.