Hepatology (Baltimore, Md.) · 2025
Selective genetic inactivation of Caspase 8 in hepatocytes ameliorates progression of MASH following Jnk deficiency.
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Volkert Ines, Grube Julia, Woitok Marius Maximilian, Mohamed Mohamed Ramadan, Edlund Karolina, Duda Julia Christin, Dietrich Jana, Schneider Ursula, Yin Guo, Lin Cheng, Erschfeld Stephanie, Berger Hilmar, Candels Lena, Davis Roger J, Bartneck Matthias, Kühnel Mark Phillip, Guillot Adrien, Schneider Kai Markus, Schneider Carolin Victoria, Jonigk Danny, Rahnenführer Jörg, Tacke Frank, Hengstler Jan, Trautwein Christian
Аннотация
BACKGROUND AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is associated with c-Jun N-terminal kinase (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 dissects its hepatocyte-specific function.
APPROACH AND RESULTS: We showed that UK Biobank patients with a predicted loss-of-function variant of JNK1 presented an increased prevalence of metabolic dysfunction-associated steatotic liver disease 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 ( Jnk1/2Δhepa ) to 2 different MASH models, we observed enhanced liver injury, fibrosis, and oxidative stress. RNA sequencing revealed highly upregulated pathways in Jnk1/2Δhepa livers, including inflammatory signals and apoptotic pathways. Additional blocking of Caspase 8 signaling improved high-fat diet-induced liver damage, fibrogenesis, and oxidative stress. Ultimately, a therapeutic approach using lipid nanoparticles containing small interfering RNA 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 the 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.
APPROACH AND RESULTS: We showed that UK Biobank patients with a predicted loss-of-function variant of JNK1 presented an increased prevalence of metabolic dysfunction-associated steatotic liver disease 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 ( Jnk1/2Δhepa ) to 2 different MASH models, we observed enhanced liver injury, fibrosis, and oxidative stress. RNA sequencing revealed highly upregulated pathways in Jnk1/2Δhepa livers, including inflammatory signals and apoptotic pathways. Additional blocking of Caspase 8 signaling improved high-fat diet-induced liver damage, fibrogenesis, and oxidative stress. Ultimately, a therapeutic approach using lipid nanoparticles containing small interfering RNA 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 the 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.