Gilglioni, E. H.; Li, A.; Saint-Pierre Wijckmans, W.; Shen, T.-K.; Perez-Chavez, I.; Hovhannisyan, G.; Lisjak, M.; Negueruela, J.; Vandenbempt, V.; Bauza-Martinez, J.; Herranz, J. M.; Ezerina, D.; Demine, S.; Feng, Z.; Vignane, T.; Otero-Sanchez, L.; Lambertucci, F.; Prasnicka, A.; Deviere, J.; Hay, D. C.; Encinar, J. A. N.; Singh, S. P.; Messens, J.; Filipovic, M. R.; Sharpe, H. J.; Trepo, E.; Wu, W.; Gurzov, E. N.

Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and positively correlated with PPAR{gamma}-induced lipogenic signalling. High-fat-fed PTPRK knockout mice displayed reduced weight gain and hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6 bisphosphatase-1 and glycolysis as PTPRK targets in metabolic reprogramming. Silencing PTPRK in hepatoma cell lines resulted in reduced colony-forming ability, and PTPRK knockout mice developed smaller tumours after diethylnitrosamine-induced hepatocarcinogenesis. Our study defines a novel role for PTPRK in regulating hepatic glycolysis, lipid metabolism, and tumour development. PTPRK inhibition may provide therapeutic possibilities in obesity-associated liver diseases.