{"doi":"10.1002/hep.32744","title":"Interleukin‐33 facilitates liver regeneration through serotonin‐involved gut‐liver axis","abstract":"BACKGROUND AND AIMS: Insufficient liver regeneration causes post-hepatectomy liver failure and small-for-size syndrome. Identifying therapeutic targets to enhance hepatic regenerative capacity remains urgent. Recently, increased IL-33 was observed in patients undergoing liver resection and in mice after partial hepatectomy (PHx). The present study aims to investigate the role of IL-33 in liver regeneration after PHx and to elucidate its underlying mechanisms. APPROACH AND RESULTS: We performed PHx in IL-33 -/- , suppression of tumorigenicity 2 (ST2) -/- , and wild-type control mice, and found deficiency of IL-33 or its receptor ST2 delayed liver regeneration. The insufficient liver regeneration could be normalized in IL-33 -/- but not ST2 -/- mice by recombinant murine IL-33 administration. Furthermore, we observed an increased level of serotonin in portal blood from wild-type mice, but not IL-33 -/- or ST2 -/- mice, after PHx. ST2 deficiency specifically in enterochromaffin cells recapitulated the phenotype of delayed liver regeneration observed in ST2 -/- mice. Moreover, the impeded liver regeneration in IL-33 -/- and ST2 -/- mice was restored to normal levels by the treatment with (±)-2,5-dimethoxy-4-iodoamphetamine, which is an agonist of the 5-hydroxytrytamine receptor (HTR)2A. Notably, in vitro experiments demonstrated that serotonin/HTR2A-induced hepatocyte proliferation is dependent on p70S6K activation. CONCLUSIONS: Our study identified that IL-33 is pro-regenerative in a noninjurious model of liver resection. The underlying mechanism involved IL-33/ST2-induced increase of serotonin release from enterochromaffin cells to portal blood and subsequent HTR2A/p70S6K activation in hepatocytes by serotonin. The findings implicate the potential of targeting the IL-33/ST2/serotonin pathway to reduce the risk of post-hepatectomy liver failure and small-for-size syndrome.","journal":"Hepatology","year":2022,"id":250757,"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":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9635,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":644457,"name":"Christoph Emontzpohl","orcid":"0000-0002-9638-3119","position":1,"is_corresponding":false},{"id":893029,"name":"Long Xu","orcid":"0000-0002-0908-1797","position":2,"is_corresponding":false},{"id":644232,"name":"Constance L. Atkins","orcid":"0000-0002-0428-1319","position":3,"is_corresponding":false},{"id":536779,"name":"Jong‐Min Jeong","orcid":"0000-0002-8440-5413","position":4,"is_corresponding":false},{"id":644455,"name":"Yang Yang","orcid":"0000-0002-0942-1800","position":5,"is_corresponding":false},{"id":893030,"name":"Kangho Kim","orcid":"0000-0001-6382-8970","position":6,"is_corresponding":false},{"id":7853,"name":"Chuan Wu","orcid":"0000-0003-2288-353X","position":7,"is_corresponding":false},{"id":3766,"name":"Shizuo Akira","orcid":"0000-0001-7602-9617","position":8,"is_corresponding":false},{"id":109413,"name":"Cynthia Ju","orcid":null,"position":9,"is_corresponding":false},{"id":109411,"name":"Yankai Wen","orcid":"0000-0002-8144-1515","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T00:24:32.960657Z","pmid":"36129070","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":[]}