{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE341nnn/GSE341199/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE341199"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Hepatocyte RIPK1 scaffolding function protects against alcohol-induced liver injury by restraining ER stress-driven apoptosis and inflammation","description":"Alcoholic liver disease (ALD) is a global health burden with limited therapeutic options. The pathogenesis of ALD involves hepatocyte death and inflammation, but the key regulatory mechanisms remain incompletely defined. Receptor-interacting protein kinase 1 (RIPK1) is a critical signaling molecule with distinct kinase-dependent and kinase-independent, scaffold-dependent functions. While RIPK1 kinase activity has been implicated in various pathologies, the role of its scaffolding function in the liver, particularly in ALD, is unknown. Here, using hepatocyte-specific RIPK1 knockout (Ripk1-hepKO) mice, we demonstrate that loss of RIPK1 markedly aggravates ethanol-induced liver injury. In both chronic and acute-binge ethanol feeding models, Ripk1-hepKO mice exhibited significantly elevated serum transaminases, enhanced hepatocyte apoptosis, and amplified hepatic inflammation with increased macrophage infiltration, without a change in steatosis. 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.","dates":{"publication":"2026/07/28"},"accession":"GSE341199","cross_references":{"GSM":["GSM9901874","GSM9901873","GSM9901872","GSM9901871","GSM9901878","GSM9901877","GSM9901876","GSM9901875"],"GPL":["24247"],"GSE":["341199"],"taxon":["Mus musculus"]}}