{"doi":"10.1016/j.jhepr.2023.100879","title":"Macrophage RIPK3 triggers inflammation and cell death via the XBP1–Foxo1 axis in liver ischaemia–reperfusion injury","abstract":"Background & AimsRIPK3 is a central player in triggering necroptotic cell death. However, whether macrophage RIPK3 may regulate NOD1-dependent inflammation and Calcineurin/TRPM7-induced hepatocyte death in oxidative stress-induced liver inflammatory injury remains elusive.MethodsA mouse model of hepatic ischemia/reperfusion injury (IRI), the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific RIPK3 knockout (RIPK3M-KO) and RIPK3-proficient (RIPK3FL/FL) mice.ResultsRIPK3M-KO diminished IR stress-induced liver damage with reduced serum ALT/AST levels, macrophage/neutrophil infiltration, and proinflammatory mediators compared to the RIPK3FL/FL controls. IR Stress activated RIPK3, IRE1α, XBP1, NOD1, NF-κB, Foxo1, Calcineurin A, and TRPM7 in ischemic livers. Conversely, RIPK3M-KO depressed IRE1α, XBP1, NOD1, Calcineurin A, and TRPM7 activation with reduced serum TNF-α levels. Moreover, Foxo1M-KO alleviated IR-induced liver injury with reduced NOD1 and TRPM7 expression. Interestingly, chromatin immunoprecipitation (ChIP) coupled with massively parallel sequencing (ChIP-Seq) revealed that macrophage Foxo1 colocalized with XBP1 and activated its target gene Zc3h15. Activating macrophage XBP1 enhanced Zc3h15, NOD1, and NF-κB activity. However, disruption of macrophage Zc3h15 inhibited NOD1 and hepatocyte Calcineurin/TRPM7 activation, with reduced ROS production and LDH release after macrophage/hepatocyte co-culture. Furthermore, adoptive transfer of Zc3h15-expressing macrophages in RIPK3M-KO mice augmented IR-triggered liver inflammation and cell death.ConclusionsMacrophage RIPK3 activates the IRE1α-XBP1 pathway and Foxo1 signaling in IR-stress livers. The XBP1-Foxo1 interaction is essential for modulating target gene Zc3h15 function, which is crucial for the control of NOD1 and Calcineurin-mediated TRPM7 activation. XBP1 functions as a transcriptional coactivator of Foxo1 in regulating NOD1-driven liver inflammation and Calcineurin/TRPM7-induced cell death. Our findings underscore a novel role of macrophage RIPK3 in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases.Lay SummaryMacrophage RIPK3 promotes NOD1-dependent inflammation and Calcineurin/TRPM7-induced cell death cascade by triggering the XBP1-Foxo1 axis and its target gene Zc3h15, which is crucial for activating NOD1 and Calcineurin/TRPM7 function, implying the potential therapeutic targets in stress-induced liver inflammatory injury.","journal":"JHEP Reports","year":2023,"id":333419,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9195,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":824959,"name":"Tao Yang","orcid":"0000-0002-1127-9364","position":1,"is_corresponding":false},{"id":1060761,"name":"Xiao Wang","orcid":"0000-0002-9647-8847","position":2,"is_corresponding":false},{"id":289494,"name":"Dongwei Xu","orcid":"0000-0001-9802-0664","position":3,"is_corresponding":false},{"id":1061199,"name":"Yeping Yu","orcid":null,"position":4,"is_corresponding":false},{"id":761224,"name":"Jun Li","orcid":"0000-0002-1961-7188","position":5,"is_corresponding":false},{"id":289496,"name":"Longfeng Jiang","orcid":"0000-0001-8058-6838","position":6,"is_corresponding":false},{"id":643940,"name":"Qiang Xia","orcid":"0000-0001-9482-6951","position":7,"is_corresponding":false},{"id":253609,"name":"Douglas G. Farmer","orcid":"0000-0001-9080-0527","position":8,"is_corresponding":false},{"id":289498,"name":"Bibo Ke","orcid":"0000-0002-1885-1538","position":9,"is_corresponding":false},{"id":1060760,"name":"X. B. Qu","orcid":"0000-0002-8202-0798","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T01:09:39.719497Z","pmid":"37841640","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}