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. 2025 Feb 26.
doi: 10.1097/HEP.0000000000001286. Online ahead of print.

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

Ines Volkert  1 , Julia Grube  1 , Marius Maximilian Woitok  1 , Mohamed Ramadan Mohamed  1 , Karolina Edlund  2 , Julia Christin Duda  3 , Jana Dietrich  4 , Ursula Schneider  4 , Guo Yin  4 , Cheng Lin  1 , Stephanie Erschfeld  1 , Hilmar Berger  5 , Lena Candels  1 , Roger J Davis  6 , Matthias Bartneck  1   7 , Mark Phillip Kühnel  4 , Adrien Guillot  5 , Kai Markus Schneider  1 , Carolin Victoria Schneider  1 , Danny Jonigk  4   8 , Jörg Rahnenführer  3 , Frank Tacke  5 , Jan Hengstler  2 , Christian Trautwein  2   9
Affiliations

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

Ines Volkert et al. Hepatology. .

Abstract

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.

Keywords: Caspase 8; apoptosis; c-Jun terminal kinases (JNK); metabolic dysfunction–associated steatohepatitis (MASH); oxidative stress.

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