| Title: | Selective genetic inactivation of Caspase 8 in hepatocytes ameliorates progression of MASH following Jnk deficiency. |
| Journal: | Hepatology |
| Published: | 26 Feb 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40009601/ |
| DOI: | https://doi.org/10.1097/hep.0000000000001286 |
Publication 15958
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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.</p>
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.</p>
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.</p>
24 Authors
- Ines Volkert
- Julia Grube
- Marius Maximilian Woitok
- Mohamed Ramadan Mohamed
- Karolina Edlund
- Julia Christin Duda
- Jana Dietrich
- Ursula Schneider
- Guo Yin
- Cheng Lin
- Stephanie Erschfeld
- Hilmar Berger
- Lena Candels
- Roger J Davis
- Matthias Bartneck
- Mark Phillip Kühnel
- Adrien Guillot
- Kai Markus Schneider
- Carolin Victoria Schneider
- Danny Jonigk
- Jörg Rahnenführer
- Frank Tacke
- Jan Hengstler
- Christian Trautwein
1 Application
| Application ID | Title |
|---|---|
| 71300 | Elucidating host-environment interactions in gastrointestinal diseases |
Enabling scientific discoveries that improve human health