The prevalence of metabolic liver disease is rising sharply, mainly driven by the causal connections between obesity, diabetes, and non-alcoholic steatohepatitis (NASH). In the absence of approved treatments, NASH represents a clear unmet medical need and an enormous economic burden for society. The development and progression of NASH is to a large extent driven by oxidative stress, originating from metabolism of excess fat. Reactive Oxygen Species (ROS) and other reactive metabolic byproducts stimulate pathological signaling through the MAP kinases (MAPK) p38 and JNK, which drive the inflammatory and fibrotic hallmarks of NASH. As a result, p38 and JNK inhibitors have been widely explored as treatments against ROS-driven diseases by the pharmaceutical industry. These efforts have been largely futile due to the multiplex biological roles of these kinases. Instead, inhibition of upstream ROS-sensing kinases hold promise for introduction of new treatment principles. An example is the ASK1 inhibitor selonsertib, which has been tested in NASH patients with limited effects. In my ERC Consolidator project “PHYRIST”, we discovered that the MAPK activating kinase ZAK also controls p38 and JNK upon oxidative stress. We showed that the impact of this signaling is especially prominent in the liver, and that ZAK knock-out (KO) mice were protected against the development of liver steatosis and mild fibrosis when fed a high fat/high sugar (HFHS) diet for 25 weeks. There is thus a good rationale for pursuing ZAK as a drug target for NASH and other metabolic diseases. In the project “NASHTARGET”, I investigated whether ZAK KO mice, either alone or in combination with ASK1 KO, were similarly protected against developing NASH-like disease when fed a recently developed and superior induction diet for only 12 weeks.
