Selective genetic inactivation of Caspase 8 in hepatocytes ameliorates progression of MASH following Jnk deficiency

Background and Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is associated with c-Jun N-terminal kinases (JNK) activation across various cell types, but its hepatocyte-specific function in steatotic liver disease remains unclear. Our study investigates the role of JNK1/JNK2 during MASH progression and dissect its hepatocyte-specific function. Approach and Results: We showed that UK biobank patients with a predicted-loss-of-function (pLOF) variant of JNK1 presented an increased prevalence of MASLD and liver damage. Analysis of a pathology cohort of patients with steatotic liver disease revealed increased oxidative stress response and apoptosis. After subjecting mice deficient for Jnk1 and Jnk2 in hepatocytes ( Jnk1/2 Δhepa ) to two different MASH models, we observed enhanced liver injury, fibrosis and oxidative stress. RNA sequencing revealed highly up-regulated pathways in Jnk1/2 Δhepa livers, including inflammatory signals and apoptotic pathways. Additional blocking of Caspase 8 signaling improved HFD-induced liver damage, fibrogenesis and oxidative stress. Ultimately, a therapeutic approach using lipid nanoparticles containing small interfering RNA (siRNA) targeting Caspase 8 during MASH progression attenuated liver injury and cell death in mice. Conclusions: Our findings define a protective role of JNK1/JNK2 in hepatocytes during the oxidative stress response driving progression of MASH. This process is mainly mediated by Caspase 8-dependent apoptosis, thereby discovering that Caspase 8 is a downstream target of JNK1/2. Caspase 8 directed therapy in hepatocytes might be a promising treatment for patients with an increased oxidative stress response and MASH.