Targeting Caspase-8 to Slow MASH Progression- Hepatology Feb.26

Metabolic dysfunction–associated steatohepatitis (MASH) is driven by oxidative stress, hepatocyte injury, inflammation, and fibrosis. Activation of the c-Jun N-terminal kinase (JNK) pathway has long been associated with MASH, but whether JNK signaling in hepatocytes is harmful or protective has remained uncertain.

This study provides an important clarification. Using human genetic data, patient liver samples, and multiple mouse models, the authors show that JNK1/JNK2 signaling in hepatocytes is protective rather than deleterious during MASH progression. In patients, loss-of-function variants in JNK1 were associated with a higher prevalence of steatotic liver disease and liver injury. In mice, selective deletion of JNK1 and JNK2 in hepatocytes unexpectedly led to worsened liver injury, fibrosis, oxidative stress, and inflammatory signaling when animals were exposed to MASH-inducing diets.

Mechanistically, the absence of hepatocyte JNK signaling resulted in marked activation of Caspase-8–dependent apoptosis, identifying Caspase-8 as a critical downstream effector driving hepatocyte death and fibrogenesis. Importantly, genetic or pharmacologic inhibition of Caspase-8 substantially improved liver injury and fibrosis, even in the setting of ongoing metabolic stress. Therapeutic silencing of Caspase-8 using lipid nanoparticle–delivered siRNA attenuated hepatocyte death and disease progression in vivo.

Overall, this work reframes JNK signaling in MASH as a stress-adaptive, hepatoprotective pathway and identifies Caspase-8 as a promising, cell-specific therapeutic target. Rather than broadly inhibiting stress pathways, selectively blocking apoptosis downstream may offer a safer and more effective strategy for patients with MASH characterized by heightened oxidative stress.