Adenosine metabolic clearance maintains liver homeostasis by licensing arginine methylation of RIPK1.

Tumor necrosis factor α (TNFα) maintains homeostasis through promoting cell survival or cell death; however, how this process is regulated by metabolic pathways remains largely unknown. Here, we identify adenosine kinase (ADK), the key enzyme for catalyzing the conversion of adenosine to AMP, as an endogenous suppressor of RIPK1 kinase. ADK-mediated adenosine metabolic clearance is a prerequisite for transmethylation reactions on various cellular targets. We found that ADK licenses constitutive R606 symmetric dimethylation in RIPK1 death domain (DD), which is catalyzed by protein arginine methyltransferase 5. Upon TNFα stimulation, DD-mediated RIPK1 dimerization is inhibited by R606 methylation, preventing RIPK1 kinase activation and keeping cell death in check. Both hepatocyte-specific ADK knockout and systemic ADK inhibition cause spontaneous RIPK1-driven hepatocyte death, which leads to hepatic homeostasis disruption. Furthermore, ADK is reduced in hepatic ischemia-reperfusion, aggravating hepatic injury during liver surgery. Thus, this study reveals a mechanism of adenosine metabolism-dependent homeostasis maintenance that is implicated in both physiological and pathological conditions.