{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:09:12Z","timestamp":1789711752285,"version":"4.0.1"},"reference-count":18,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"\n Background<\/jats:title>\n Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic disorders in which dysregulated apoptosis, oxidative stress, and adaptive survival signaling contribute to disease persistence and therapeutic resistance. Venetoclax (VEN) targets BCL-2-dependent survival, but resistance is frequently accompanied by compensatory survival programs. Whether ferroptosis-associated transcriptional states are dynamically remodeled during VEN treatment and participate in this adaptive phenotype remains incompletely understood.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We analyzed two independent human MDS single-cell RNA-sequencing cohorts together with an\n in vitro<\/jats:italic>\n VEN-resistant MDS-L model. GSE241417 was used to characterize longitudinal and cell-state-specific ferroptosis-associated transcriptional patterns, whereas GSE180298 provided independent single-cell validation. Longitudinal module scores were summarized across major hematopoietic states and treatment stages. Apoptosis\/proliferation- and ferroptosis-related genes were further examined by qRT-PCR in parental and VEN-resistant MDS-L cells.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Single-cell analysis revealed marked heterogeneity of ferroptosis-associated transcriptional programs across MDS hematopoietic populations. Longitudinal trajectories in GSE241417 demonstrated nonuniform, treatment-stage- and cell-state-dependent remodeling of ferroptosis balance, inflammatory context, and survival-associated programs. The independent GSE180298 cohort reproduced major disease-associated ferroptosis-related transcriptional differences. In VEN-resistant MDS-L cells,\n MCL1<\/jats:italic>\n ,\n BCL2L1<\/jats:italic>\n ,\n MKI67<\/jats:italic>\n ,\n GPX4<\/jats:italic>\n ,\n SLC7A11<\/jats:italic>\n , and\n NFE2L2<\/jats:italic>\n were increased, whereas\n BCL2<\/jats:italic>\n ,\n DDIT3<\/jats:italic>\n ,\n ACSL4<\/jats:italic>\n , and\n NCOA4<\/jats:italic>\n were decreased, indicating coordinated adaptation of apoptotic and ferroptosis-related pathways.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n This study reveals cell-state-dependent and temporally dynamic ferroptosis-associated remodeling in MDS and identifies a coordinated apoptosis-redox transcriptional program associated with VEN resistance. The integration of longitudinal single-cell analysis, independent single-cell validation, and targeted qRT-PCR supports ferroptosis-defense pathways as a biologically relevant component of VEN-resistant adaptation and provides a rationale for future combination strategies that address both apoptotic dependence and redox-state plasticity.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fcell.2026.1947721","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:37:58Z","timestamp":1789709878000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-cell transcriptomic characterization of a human MDS hematopoietic dataset and in vitro validation of apoptosis-related venetoclax resistance in human MDS-L cells"],"prefix":"10.3389","volume":"14","author":[{"given":"Tianjiao","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Hematology, Qiqihar Medical University (The Second Affiliated Hospital)","place":["Qiqihar, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyu","family":"Li","sequence":"additional","affiliation":[{"name":"Clinical Pathology Professional College, General Graduate School of Kyungwoon University","place":["Gumi, North Gyeongsang, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Hematology, Qiqihar Medical University (The Second Affiliated Hospital)","place":["Qiqihar, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Hematology, Qiqihar Medical University (The Second Affiliated Hospital)","place":["Qiqihar, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suliang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Qiqihar Medical University (The Second Affiliated Hospital)","place":["Qiqihar, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e756","DOI":"10.1016\/S2352-3026(22)00216-2","article-title":"Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1\u20132 study","volume":"9","author":"Bazinet","year":"2022","journal-title":"Lancet Haematol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2026","DOI":"10.1080\/10428194.2017.1283032","article-title":"Pathways and mechanisms of venetoclax resistance","volume":"58","author":"Bose","year":"2017","journal-title":"Leuk. 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