{"doi":"10.1089/ars.2024.0882","title":"Exosomal miR-196a-5p Secreted by Bone Marrow Mesenchymal Stem Cells Inhibits Ferroptosis and Promotes Drug Resistance of Acute Myeloid Leukemia","abstract":"<jats:sec>\n                    <jats:title>Background:</jats:title>\n                    <jats:p>Ferroptosis is a nonapoptotic type of cell death characterized by an increase in lipid reactive oxygen species (ROS). Acute myeloid leukemia (AML)–derived bone marrow mesenchymal stem cells (AML-BMSCs) support the progression and drug resistance of AML by secreting various bioactive substances, including exosomes. However, the role of BMSCs in regulating lipid metabolism and ferroptosis in AML remains unexplored.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:</jats:title>\n                    <jats:p>Exosomes secreted by AML-BMSCs increased the expression of miR-196a-5p in AML cells. MiR-196a-5p promoted the proliferation of AML cells, reduced lipid ROS and ferroptosis, and was associated with poor prognosis in AML patients. Mechanistically, miR-196a-5p inhibited the expression level of neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L). Co-immunoprecipitation (CO-IP) analysis showed that NEDD4L was bound to long-chain acyl-CoA synthetase (ACSL)3 and promoted ubiquitin-mediated degradation of ACSL3 protein. In addition, we also demonstrated that AML-BMSCs highly expressed Ras-associated binding protein 7A (RAB7A), which was associated with exosomal miR-196a-5p release. Importantly, cytarabine (Ara-C) activated the expression of RAB7A and promoted the secretion of exosomal miR-196a-5p, which weakened the ubiquitination of ACSL3 by NEDD4L, leading to ferroptosis inhibition and Ara-C resistance in AML.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Innovation:</jats:title>\n                    <jats:p>This is the first time that exosomes secreted by BMSCs (BMSCs-exos) have been linked to ferroptosis in AML cells, thereby expanding our understanding of the mechanism of drug resistance in AML cells. High miR-196a-5p expression reduced lipid ROS levels and ferroptosis in AML cells by inhibiting NEDD4L-mediated ubiquitination of ACSL3.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:</jats:title>\n                    <jats:p>\n                      This study identified a new network through which BMSCs-exos regulate ferroptosis in AML cells. We combined BMSCs and AML cells to provide new ideas for drug research targeting exosome secretion and ferroptosis.\n                      <jats:italic toggle=\"yes\">Antioxid. Redox Signal.</jats:italic>\n                      42, 933–953.\n                    </jats:p>\n                  </jats:sec>","journal":"Antioxidants &amp; Redox Signaling","year":2025,"id":645360,"datarank":0.37273599746820013,"base_score":2.4849066497880004,"endowment":2.4849066497880004,"self_citation_contribution":0.37273599746820013,"citation_network_contribution":0.0,"self_endowment_contribution":0.37273599746820013,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"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":369149,"name":"Li Wang","orcid":"0000-0002-4007-6654","position":1,"is_corresponding":false},{"id":1680391,"name":"Tianzhen Hu","orcid":null,"position":2,"is_corresponding":false},{"id":1030641,"name":"Lin Zheng","orcid":"0000-0002-7585-6968","position":3,"is_corresponding":false},{"id":1680392,"name":"Jishi Wang","orcid":null,"position":4,"is_corresponding":false},{"id":1680390,"name":"Bingjie Fan","orcid":"0000-0002-7528-359X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Exosomal miR-196a-5p Secreted by Bone Marrow Mesenchymal Stem Cells Inhibits Ferroptosis and Promotes Drug Resistance of Acute Myeloid Leukemia","abstract":"<jats:sec>\n                    <jats:title>Background:</jats:title>\n                    <jats:p>Ferroptosis is a nonapoptotic type of cell death characterized by an increase in lipid reactive oxygen species (ROS). Acute myeloid leukemia (AML)–derived bone marrow mesenchymal stem cells (AML-BMSCs) support the progression and drug resistance of AML by secreting various bioactive substances, including exosomes. However, the role of BMSCs in regulating lipid metabolism and ferroptosis in AML remains unexplored.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:</jats:title>\n                    <jats:p>Exosomes secreted by AML-BMSCs increased the expression of miR-196a-5p in AML cells. MiR-196a-5p promoted the proliferation of AML cells, reduced lipid ROS and ferroptosis, and was associated with poor prognosis in AML patients. Mechanistically, miR-196a-5p inhibited the expression level of neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L). Co-immunoprecipitation (CO-IP) analysis showed that NEDD4L was bound to long-chain acyl-CoA synthetase (ACSL)3 and promoted ubiquitin-mediated degradation of ACSL3 protein. In addition, we also demonstrated that AML-BMSCs highly expressed Ras-associated binding protein 7A (RAB7A), which was associated with exosomal miR-196a-5p release. Importantly, cytarabine (Ara-C) activated the expression of RAB7A and promoted the secretion of exosomal miR-196a-5p, which weakened the ubiquitination of ACSL3 by NEDD4L, leading to ferroptosis inhibition and Ara-C resistance in AML.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Innovation:</jats:title>\n                    <jats:p>This is the first time that exosomes secreted by BMSCs (BMSCs-exos) have been linked to ferroptosis in AML cells, thereby expanding our understanding of the mechanism of drug resistance in AML cells. High miR-196a-5p expression reduced lipid ROS levels and ferroptosis in AML cells by inhibiting NEDD4L-mediated ubiquitination of ACSL3.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:</jats:title>\n                    <jats:p>\n                      This study identified a new network through which BMSCs-exos regulate ferroptosis in AML cells. We combined BMSCs and AML cells to provide new ideas for drug research targeting exosome secretion and ferroptosis.\n                      <jats:italic toggle=\"yes\">Antioxid. Redox Signal.</jats:italic>\n                      42, 933–953.\n                    </jats:p>\n                  </jats:sec>","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":"40388337","pmcid":null,"openalex_id":"https://openalex.org/W4410493878","authors":[],"funders":[],"total_grants":0,"fwci":4.2384,"citation_percentile":0.94789679,"influential_citations":0,"citation_trend":[{"year":2025,"count":4},{"year":2026,"count":6}],"oa_status":"closed","license":"https://journals.sagepub.com/page/policies/text-and-data-mining-license","oa_locations":[{"url":"https://journals.sagepub.com/doi/full-xml/10.1089/ars.2024.0882","host_type":"publisher"},{"url":"https://journals.sagepub.com/doi/pdf/10.1089/ars.2024.0882","host_type":"publisher"},{"url":"https://doi.org/10.1089/ars.2024.0882","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40388337","host_type":"repository"}],"fields_of_study":["Extracellular vesicles in disease","MicroRNA in disease regulation","Circular RNAs in diseases","Ferroptosis","Humans","MicroRNAs","Mesenchymal Stem Cells","Leukemia, Myeloid, Acute","Exosomes","Drug Resistance, Neoplasm","Animals","Mice","Reactive Oxygen Species","Male","Female","Cell Line, Tumor","Coenzyme A Ligases"],"mesh_terms":["Ferroptosis","Animals","Coenzyme A Ligases","Female","Humans","Male","Leukemia, Myeloid, Acute","Reactive Oxygen Species","Drug Resistance, Neoplasm","MicroRNAs","Cell Line, Tumor","Mice","Exosomes","Mesenchymal Stem Cells"],"keywords":["Myeloid leukemia","Mesenchymal stem cell","Cancer research","Bone marrow","Drug resistance","Leukemia","Stem cell","Medicine","Drug","Immunology","Cell biology","Biology","Pharmacology","Pathology","Microbiology","AMl","Exosome","Bone marrow mesenchymal stem cells","Ferroptosis","Mir-196a-5p"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T05:05:01.852138Z","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":[]}