{"doi":"10.1038/s42003-024-06427-8","title":"IL-37d suppresses Rheb-mTORC1 axis independently of TCS2 to alleviate alcoholic liver disease","abstract":"<jats:title>Abstract</jats:title><jats:p>Tuberous sclerosis complex 2 (TSC2) crucially suppresses Rheb activity to prevent mTORC1 activation. However, mutations in TSC genes lead to mTORC1 overactivation, thereby causing various developmental disorders and cancer. Therefore, the discovery of novel Rheb inhibitors is vital to prevent mTOR overactivation. Here, we reveals that the anti-inflammatory cytokine IL-37d can bind to lysosomal Rheb and suppress its activity independent of TSC2, thereby preventing mTORC1 activation. The binding of IL-37d to Rheb switch-II subregion destabilizes the Rheb-mTOR and mTOR-S6K interactions, further halting mTORC1 signaling. Unlike TSC2, IL-37d is reduced under ethanol stimulation, which results in mitigating the suppression of lysosomal Rheb-mTORC1 activity. Consequently, the recombinant human IL-37d protein (rh-IL-37d) with a TAT peptide greatly improves alcohol-induced liver disorders by hindering Rheb-mTORC1 axis overactivation in a TSC2- independent manner. Together, IL-37d emerges as a novel Rheb suppressor independent of TSC2 to terminate mTORC1 activation and improve abnormal lipid metabolism in the liver.</jats:p>","journal":"Communications Biology","year":2024,"id":658340,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1330596,"name":"Xiaoyu Wang","orcid":"0009-0009-8943-131X","position":1,"is_corresponding":false},{"id":1084676,"name":"Yaxin Guo","orcid":"0000-0003-2943-5203","position":2,"is_corresponding":false},{"id":629982,"name":"Ming Zhao","orcid":"0000-0002-5700-2950","position":3,"is_corresponding":false},{"id":1085230,"name":"Baihui Cao","orcid":null,"position":4,"is_corresponding":false},{"id":1085231,"name":"Bing Zhan","orcid":null,"position":5,"is_corresponding":false},{"id":665419,"name":"Yubin Li","orcid":null,"position":6,"is_corresponding":false},{"id":779757,"name":"Tian Zhou","orcid":null,"position":7,"is_corresponding":false},{"id":276185,"name":"Faliang Zhu","orcid":null,"position":8,"is_corresponding":false},{"id":297893,"name":"Chun Guo","orcid":"0000-0002-1540-3166","position":9,"is_corresponding":false},{"id":347453,"name":"Yongyu Shi","orcid":"0000-0003-1356-3219","position":10,"is_corresponding":false},{"id":347451,"name":"Qun Wang","orcid":"0000-0002-2841-2651","position":11,"is_corresponding":false},{"id":349327,"name":"Lining Zhang","orcid":"0000-0002-7563-6957","position":12,"is_corresponding":false},{"id":418221,"name":"Yan Li","orcid":"0000-0002-7884-8074","position":13,"is_corresponding":false},{"id":1084675,"name":"Nuo Chen","orcid":"0009-0000-2895-746X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"IL-37d suppresses Rheb-mTORC1 axis independently of TCS2 to alleviate alcoholic liver disease","abstract":"<jats:title>Abstract</jats:title><jats:p>Tuberous sclerosis complex 2 (TSC2) crucially suppresses Rheb activity to prevent mTORC1 activation. However, mutations in TSC genes lead to mTORC1 overactivation, thereby causing various developmental disorders and cancer. Therefore, the discovery of novel Rheb inhibitors is vital to prevent mTOR overactivation. Here, we reveals that the anti-inflammatory cytokine IL-37d can bind to lysosomal Rheb and suppress its activity independent of TSC2, thereby preventing mTORC1 activation. The binding of IL-37d to Rheb switch-II subregion destabilizes the Rheb-mTOR and mTOR-S6K interactions, further halting mTORC1 signaling. Unlike TSC2, IL-37d is reduced under ethanol stimulation, which results in mitigating the suppression of lysosomal Rheb-mTORC1 activity. Consequently, the recombinant human IL-37d protein (rh-IL-37d) with a TAT peptide greatly improves alcohol-induced liver disorders by hindering Rheb-mTORC1 axis overactivation in a TSC2- independent manner. Together, IL-37d emerges as a novel Rheb suppressor independent of TSC2 to terminate mTORC1 activation and improve abnormal lipid metabolism in the liver.</jats:p>","is_dataset_classified":null,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38907105","pmcid":"PMC11192940","openalex_id":"https://openalex.org/W4399889876","authors":[],"funders":[{"funder_name":"The National Natural Science Foundation of China.","grant_id":"","title":null}],"total_grants":1,"fwci":2.3706,"citation_percentile":0.89289126,"influential_citations":0,"citation_trend":[{"year":2025,"count":6},{"year":2026,"count":4}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.nature.com/articles/s42003-024-06427-8.pdf","host_type":"journal"},{"url":"https://www.nature.com/articles/s42003-024-06427-8.pdf","host_type":"publisher"},{"url":"https://www.nature.com/articles/s42003-024-06427-8","host_type":"publisher"},{"url":"https://doi.org/10.1038/s42003-024-06427-8","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38907105","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11192940","host_type":"repository"},{"url":"https://doaj.org/article/642c79be80334573bdcf7898b8170d4e","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11192940","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11192940?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Tuberous Sclerosis Complex Research","PI3K/AKT/mTOR signaling in cancer","Mast cells and histamine","Mechanistic Target of Rapamycin Complex 1","Ras Homolog Enriched in Brain Protein","Humans","Animals","Mice","Signal Transduction","Tuberous Sclerosis Complex 2 Protein","Liver Diseases, Alcoholic","Interleukin-1","Mice, Inbred C57BL","Male","HEK293 Cells"],"mesh_terms":["Ras Homolog Enriched in Brain Protein","Mechanistic Target of Rapamycin Complex 1","Tuberous Sclerosis Complex 2 Protein","Animals","Humans","Interleukin-1","Liver Diseases, Alcoholic","Male","Mice, Inbred C57BL","Signal Transduction","Mice","HEK293 Cells"],"keywords":["RHEB","mTORC1","TSC2","TSC1","PI3K/AKT/mTOR pathway","Cancer research","Cell biology","Mechanistic target of rapamycin","Biology","Chemistry","Signal transduction"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"uniprot"},{"name":"pdb"},{"name":"doi"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-12T03:55:20.539644Z","pmid":null,"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":[]}