{"doi":"10.1016/j.canlet.2025.217870","title":"Targeting the cholinergic-astrocyte axis: A novel strategy for brain metastasis prevention in lung adenocarcinoma","abstract":null,"journal":"Cancer Letters","year":2025,"id":611970,"datarank":0.36293829087934326,"base_score":2.302585092994046,"endowment":2.302585092994046,"self_citation_contribution":0.3453877639491069,"citation_network_contribution":0.017550526930236347,"self_endowment_contribution":0.3453877639491069,"citer_contribution":0.017550526930236347,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":9,"citers_with_citation_signal":2,"citers_with_endowment":2,"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":1494003,"name":"Kun Liu","orcid":"0000-0003-1366-4546","position":1,"is_corresponding":false},{"id":132308,"name":"Ziyao Zhang","orcid":"0000-0003-3219-9221","position":2,"is_corresponding":false},{"id":1575399,"name":"Wangyang Zhu","orcid":null,"position":3,"is_corresponding":false},{"id":640174,"name":"Miao Zhao","orcid":"0009-0003-3607-5215","position":4,"is_corresponding":false},{"id":304631,"name":"Dan Zhao","orcid":"0000-0002-5749-1467","position":5,"is_corresponding":false},{"id":264363,"name":"Yue Zhao","orcid":"0000-0003-3645-2634","position":6,"is_corresponding":false},{"id":887376,"name":"Yang Zhang","orcid":"0000-0003-3383-7889","position":7,"is_corresponding":false},{"id":1575402,"name":"Fangqiu Fu","orcid":null,"position":8,"is_corresponding":false},{"id":108247,"name":"Haiquan Chen","orcid":"0000-0001-7846-257X","position":9,"is_corresponding":false},{"id":1575397,"name":"Xiangze Li","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Targeting the cholinergic-astrocyte axis: A novel strategy for brain metastasis prevention in lung adenocarcinoma","abstract":"Brain metastasis (BM) represents a highly detrimental complication of lung adenocarcinoma (LUAD), persisting even following curative resection of primary tumors, with limited effective preventive measures. This study explores the role of cholinergic metabolism, a pathway crucial for both LUAD progression and brain function, in the pathogenesis of BM. Through comprehensive analysis of RNA-sequencing data from 875 LUAD cases and validation using tissue microarrays from 280 patients, we identified cholinergic metabolic activation as a defining characteristic of tumors prone to BM, which is significantly associated with poor survival outcomes. Mechanistic investigations revealed that acetylcholinesterase (AChE) facilitates BM via dual pro-metastatic mechanisms: immunosuppression and disruption of the blood-brain barrier (BBB). Specifically, AChE-induced overactivation of cholinergic receptors triggers excessive Ca<sup>2+</sup> influx, leading to ATP release and astrocyte apoptosis, thereby promoting tumor extravasation across the BBB. Furthermore, choline acetyltransferase enhances tumor aggressiveness by stimulating proliferation and migration. Single-cell RNA sequencing of 26 BM sites and 8 normal brain samples, corroborated by in vitro experiments, elucidated tumor-mediated alterations in the BBB and immune cells. Notably, pharmacological intervention with the AChE inhibitor donepezil exhibited substantial efficacy in preventing BM. Collectively, these findings uncover a targetable cholinergic metabolism-astrocyte axis governing BM organotropism, providing a transformative strategy to intercept metastatic progression in LUAD.","is_dataset_classified":null,"base_score":2.302585092994046,"endowment":2.302585092994046,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40516905","pmcid":null,"openalex_id":"https://openalex.org/W4411329352","authors":[],"funders":[{"funder_name":"National Key Research and Development Program of China Stem Cell and Translational Research","grant_id":"2022YFA1103900","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"82203037","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"82373309","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81930073","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"82102914","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"82430099","title":null},{"funder_name":"Shanghai Municipal Natural Science Foundation","grant_id":"22YF1408900","title":null},{"funder_name":"National Key Research and Development Program of China","grant_id":"","title":null},{"funder_name":"Shanghai Lingjun Program","grant_id":"","title":null}],"total_grants":9,"fwci":3.6664,"citation_percentile":0.93643055,"influential_citations":0,"citation_trend":[{"year":2025,"count":1},{"year":2026,"count":8}],"oa_status":"closed","license":"https://doi.org/10.15223/policy-004","oa_locations":[{"url":"https://api.elsevier.com/content/article/PII:S0304383525004379?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0304383525004379?httpAccept=text/plain","host_type":"publisher"},{"url":"https://doi.org/10.1016/j.canlet.2025.217870","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40516905","host_type":"repository"}],"fields_of_study":["Nicotinic Acetylcholine Receptors Study","Brain Metastases and Treatment","Cancer, Stress, Anesthesia, and Immune Response","Humans","Brain Neoplasms","Adenocarcinoma of Lung","Astrocytes","Lung Neoplasms","Blood-Brain Barrier","Animals","Acetylcholinesterase","Cell Line, Tumor","Cholinesterase Inhibitors","Female","Male","Donepezil","Mice","Cell Proliferation","Apoptosis","Cell Movement"],"mesh_terms":["Adenocarcinoma of Lung","Donepezil","Acetylcholinesterase","Animals","Astrocytes","Blood-Brain Barrier","Brain Neoplasms","Cell Movement","Cholinesterase Inhibitors","Female","Humans","Lung Neoplasms","Male","Apoptosis","Cell Line, Tumor","Cell Proliferation","Mice"],"keywords":["Cholinergic","Choline acetyltransferase","Brain metastasis","Astrocyte","Cancer research","Adenocarcinoma","Medicine","Metastasis","Brain tumor","Biology","Pathology","Cancer","Internal medicine","Central nervous system","Prevention","Lung adenocarcinoma","Cholinergic Metabolism"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"No poverty"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T00:24:02.419033Z","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":[]}