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

• Volkert, I.
• Grube, J.
• Woitok, M. M.
• Mohamed, M. R.
• Edlund, K.
• Duda, J. C.
• Dietrich, J.
• Schneider, U.
• Yin, G.
• Lin, C.
• Erschfeld, S.
• Berger, H.
• Candels, L.
• Davis, R. J.
• Bartneck, M.
• Kühnel, M. P.
• Guillot, A.
• Schneider, K. M.
• Schneider, C. V.
• Jonigk, D.
• Rahnenführer, J.
• Tacke, F.
• Hengstler, J.
• Trautwein, C.