Hepatocyte RIPK1 scaffolding function protects against alcohol-induced liver injury by restraining ER stress-driven apoptosis and inflammation

Transcriptomic analysis revealed enrichment of inflammatory pathways in Ripk1-hepKO livers. Mechanistically, we identified endoplasmic reticulum (ER) stress as a critical contributor to this phenotype. RIPK1 deficiency was associated with attenuated NF-κB/p65 signaling, preferential amplification of eIF2α-ATF4-CHOP-associated stress responses, and enhanced CHOP accumulation, while pharmacological modulation of ER stress-associated pathways using 4-phenylbutyrate (4-PBA) or ISRIB ameliorated hepatocyte apoptosis, liver injury, and inflammation in ethanol-fed Ripk1-hepKO mice.

Translating these findings to human disease, liver specimens from ALD patients showed elevated hepatocyte apoptosis, CD68+ macrophage infiltration, and induction of ER stress markers. Our study unveils a previously unrecognized protective role for the scaffold function of hepatocyte RIPK1 in ALD, positioning RIPK1 scaffolding and ER stress-associated signaling as promising therapeutic targets for ALD.