{"doi":"10.3389/fgene.2026.1720829","title":"ORMDL3: from an asthma susceptibility gene to multi-disease associations","abstract":"<jats:p>\n                    The ORMDL3 protein, encoded by the\n                    <jats:italic>ORMDL3</jats:italic>\n                    gene, functions as a transmembrane protein in the endoplasmic reticulum. Initially identified through its genetic link to asthma susceptibility, ORMDL3 plays a key role in regulating sphingolipid metabolism by inhibiting Serine Palmitoyltransferase activity. This regulation influences the synthesis of bioactive lipids like ceramides, which in turn affect cellular homeostasis, inflammatory responses, and immune regulation. Recent studies show that ORMDL3’s function extends beyond the respiratory system, with involvement in obesity, diabetes, atherosclerosis, inflammatory bowel disease, autoimmune diseases, and various cancers. It regulates processes such as endoplasmic reticulum stress, the unfolded protein response, autophagy, calcium signaling, and inflammatory pathways. This review highlights ORMDL3’s expression patterns, molecular mechanisms, and clinical relevance across different diseases, emphasizing its role as a biological node linking multiple pathologies. Additionally, it discusses ORMDL3’s potential as a target for innovative therapies and diagnostic biomarkers, laying the groundwork for future interdisciplinary research and precision medicine applications.\n                  </jats:p>","journal":"Frontiers in Genetics","year":2026,"id":608433,"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":0,"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":1562707,"name":"Siyi Guo","orcid":null,"position":1,"is_corresponding":false},{"id":364191,"name":"Chao Wang","orcid":"0000-0002-8054-3472","position":2,"is_corresponding":false},{"id":1562708,"name":"Yewen Niu","orcid":null,"position":3,"is_corresponding":false},{"id":411103,"name":"Jiayi Liu","orcid":"0000-0001-6432-0124","position":4,"is_corresponding":false},{"id":1562709,"name":"Kaifeng Li","orcid":null,"position":5,"is_corresponding":false},{"id":676829,"name":"Dong Li","orcid":"0000-0002-7729-7151","position":6,"is_corresponding":false},{"id":1346279,"name":"Fei Yu","orcid":"0000-0002-4604-7002","position":7,"is_corresponding":false},{"id":847735,"name":"Xuan Li","orcid":"0000-0003-1768-9556","position":8,"is_corresponding":false},{"id":1562706,"name":"Zichao Han","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"ORMDL3: from an asthma susceptibility gene to multi-disease associations","abstract":"<jats:p>\n                    The ORMDL3 protein, encoded by the\n                    <jats:italic>ORMDL3</jats:italic>\n                    gene, functions as a transmembrane protein in the endoplasmic reticulum. Initially identified through its genetic link to asthma susceptibility, ORMDL3 plays a key role in regulating sphingolipid metabolism by inhibiting Serine Palmitoyltransferase activity. This regulation influences the synthesis of bioactive lipids like ceramides, which in turn affect cellular homeostasis, inflammatory responses, and immune regulation. Recent studies show that ORMDL3’s function extends beyond the respiratory system, with involvement in obesity, diabetes, atherosclerosis, inflammatory bowel disease, autoimmune diseases, and various cancers. It regulates processes such as endoplasmic reticulum stress, the unfolded protein response, autophagy, calcium signaling, and inflammatory pathways. This review highlights ORMDL3’s expression patterns, molecular mechanisms, and clinical relevance across different diseases, emphasizing its role as a biological node linking multiple pathologies. Additionally, it discusses ORMDL3’s potential as a target for innovative therapies and diagnostic biomarkers, laying the groundwork for future interdisciplinary research and precision medicine applications.\n                  </jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41884618","pmcid":"PMC13010176","openalex_id":"https://openalex.org/W7138298600","authors":[],"funders":[],"total_grants":0,"fwci":0.0,"citation_percentile":0.25546502,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://public-pages-files-2025.frontiersin.org/journals/genetics/articles/10.3389/fgene.2026.1720829/pdf","host_type":"journal"},{"url":"https://public-pages-files-2025.frontiersin.org/journals/genetics/articles/10.3389/fgene.2026.1720829/pdf","host_type":"publisher"},{"url":"https://www.frontiersin.org/articles/10.3389/fgene.2026.1720829/full","host_type":"publisher"},{"url":"https://doi.org/10.3389/fgene.2026.1720829","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41884618","host_type":"repository"},{"url":"https://doaj.org/article/583886c87e774545b0bf58e7c47fefc4","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13010176/","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC13010176","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC13010176?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Sphingolipid Metabolism and Signaling","Endoplasmic Reticulum Stress and Disease","Inflammasome and immune disorders"],"mesh_terms":[],"keywords":["Endoplasmic reticulum","Immune system","Transmembrane protein","Unfolded protein response","Gene","Sphingolipid","Function (biology)","Asthma","Inflammation","Review","Ormdl3","Multi-Disease Associations"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"refsnp"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-30T14:24:35.870813Z","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":[]}