{"doi":"10.1016/j.molcel.2025.12.017","title":"ICAM1 mRNA entraps ILF2/ILF3 to inhibit transcription of EIF4E and global protein synthesis","abstract":"The view of mRNA function as a translational template is being challenged beyond translation. However, how these non-canonical mRNAs function independently of their coding protein remains largely unexplored. Here, we found that intercellular adhesion molecule 1 (ICAM1) depletion via CRISPR-Cas9 protein knockout and shRNA-mediated RNA knockdown produces opposite effects on cell proliferation in human cells, which is validated by overexpression of mutated coding ICAM1 mRNA and ICAM1 coding sequence (CDS). Mechanistically, cis-antisense transcripts of ICAM1/ICAM1-AS form a double-stranded RNA (dsRNA), which entraps the interleukin enhancer binding factor 2 (ILF2)/ILF3 complex to inhibit DNA binding in a length-dependent manner, thus suppressing EIF4E transcription and global protein synthesis. Clinical analysis highlights the coordinated downregulation of ICAM1/ICAM1-AS, independent of highly expressed ICAM1 protein in lung cancer. In conclusion, this study reveals a role for ICAM1 mRNA in regulating cellular transcription via the dsRNA-ILF2/3 axis. Our findings challenge the phenotype explanation of gene silencing between RNA knockdown and protein knockout and underscore independent mRNA functions.","journal":"Molecular Cell","year":2026,"id":11449,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0422,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2026-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":91834,"name":"Jinghan Sun","orcid":null,"position":1,"is_corresponding":false},{"id":91835,"name":"Ya Gao","orcid":"0000-0003-2244-7834","position":2,"is_corresponding":false},{"id":44485,"name":"Haifeng Zhang","orcid":null,"position":3,"is_corresponding":false},{"id":89579,"name":"Ying He","orcid":"0000-0002-8857-3545","position":4,"is_corresponding":false},{"id":91836,"name":"Yibi Zhang","orcid":null,"position":5,"is_corresponding":false},{"id":91837,"name":"Zhiyuan Xu","orcid":null,"position":6,"is_corresponding":false},{"id":91838,"name":"Shuwen Cheng","orcid":"0000-0002-0365-7935","position":7,"is_corresponding":false},{"id":91839,"name":"Hong Yan","orcid":"0000-0001-9661-3095","position":8,"is_corresponding":false},{"id":91840,"name":"Liqiang Duan","orcid":null,"position":9,"is_corresponding":false},{"id":4389,"name":"Peng Xu","orcid":"0000-0001-8007-9879","position":10,"is_corresponding":false},{"id":91841,"name":"Qinong Ye","orcid":"0000-0001-8032-8919","position":11,"is_corresponding":false},{"id":80355,"name":"Shan Gao","orcid":"0009-0002-1705-8033","position":12,"is_corresponding":false},{"id":91842,"name":"Su Lin","orcid":"0000-0001-7517-9859","position":13,"is_corresponding":false},{"id":91833,"name":"Siyuan Jiang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-03-01T18:20:47.508186Z","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":[]}