{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T05:09:07Z","timestamp":1779426547878,"version":"3.53.1"},"reference-count":17,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"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. Oncol."],"abstract":"\n Ferroptosis, an iron-dependent form of regulated cell death driven by lethal lipid peroxidation, has emerged as a targetable vulnerability in cancer.\n ACSL4<\/jats:italic>\n is the rate-limiting enzyme that dictates ferroptosis sensitivity by channeling polyunsaturated fatty acids into membrane phospholipids. In acute myeloid leukemia (AML), monocytic subtypes resist BCL2 inhibition with venetoclax, yet their metabolic dependencies remain poorly defined. Here, we integrated PRISM drug-sensitivity data (6,790 compounds) and DepMap CRISPR dependencies (18,435 genes) across 15 adult AML cell lines to map drug-gene co-dependencies. A multi-cohort validation strategy \u2014 filtering 50 discovery candidates (29 testable in BeatAML) through\n ex vivo<\/jats:italic>\n drug-response data in 476 primary AML specimens and clinical outcomes in 140 adults with\n de novo<\/jats:italic>\n AML (TCGA-LAML) \u2014 converged on a single axis linking SRC family kinase inhibition to\n ACSL4<\/jats:italic>\n expression.\n ACSL4<\/jats:italic>\n -high blasts showed enhanced dasatinib sensitivity (\n r<\/jats:italic>\n \u00a0=\u00a0-0.25,\n P<\/jats:italic>\n \u00a0=\u00a04.3 x 10\n -8<\/jats:sup>\n ). A composite\n SRC<\/jats:italic>\n \/\n ACSL4<\/jats:italic>\n signature stratified overall survival (HR 1.27; 95% CI 1.10-1.47;\n P<\/jats:italic>\n \u00a0=\u00a00.0014), remaining significant after age adjustment. Single-cell atlas projection localized this signature to the monocytic compartment. The\n SRC<\/jats:italic>\n \/\n ACSL4<\/jats:italic>\n -high state displayed a ferroptosis gene expression profile characterized by co-upregulation of\n ACSL4<\/jats:italic>\n ,\n HMOX1<\/jats:italic>\n , and\n LPCAT3<\/jats:italic>\n with failure to upregulate the principal ferroptosis defense axis\n GPX4<\/jats:italic>\n \/\n SLC7A11<\/jats:italic>\n . Conversely,\n ACSL4<\/jats:italic>\n -high blasts showed significant\n ex vivo<\/jats:italic>\n resistance to venetoclax (\n r<\/jats:italic>\n \u00a0=\u00a00.36,\n P<\/jats:italic>\n \u00a0=\u00a02.5 x 10\n -12<\/jats:sup>\n ), linking the ferroptosis-primed monocytic state to BCL2 inhibitor failure. These findings nominate\n ACSL4<\/jats:italic>\n -driven ferroptosis susceptibility as a lineage-specific vulnerability rendering monocytic AML selectively sensitive to SRC-directed therapy while resistant to BCL2 inhibition.\n <\/jats:p>","DOI":"10.3389\/fonc.2026.1837940","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T04:45:33Z","timestamp":1779425133000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ACSL4-driven ferroptosis susceptibility as a targetable vulnerability in monocytic acute myeloid leukemia"],"prefix":"10.3389","volume":"16","author":[{"given":"Federico","family":"De Marchi","sequence":"first","affiliation":[{"name":"Department of Hematology, Veneto Institute of Oncology IOV \u2013 IRCCS","place":["Padua, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Gottardi","sequence":"additional","affiliation":[{"name":"Department of Hematology, Veneto Institute of Oncology IOV \u2013 IRCCS","place":["Padua, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: an iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00324-8","article-title":"Ferroptosis: mechanisms, biology and role in disease","volume":"22","author":"Jiang","year":"2021","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2239","article-title":"ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition","volume":"13","author":"Doll","year":"2017","journal-title":"Nat Chem Biol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nature23007","article-title":"Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway","volume":"547","author":"Viswanathan","year":"2017","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nature24297","article-title":"Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition","volume":"551","author":"Hangauer","year":"2017","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2012971","article-title":"Azacitidine and venetoclax in previously untreated acute myeloid leukemia","volume":"383","author":"DiNardo","year":"2020","journal-title":"N Engl J Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-19-0710","article-title":"Monocytic subclones confer resistance to venetoclax-based therapy in patients with acute myeloid leukemia","volume":"10","author":"Pei","year":"2020","journal-title":"Cancer Discov"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-019-0018-6","article-title":"Discovering the anticancer potential of non-oncology drugs by systematic viability profiling","volume":"1","author":"Corsello","year":"2020","journal-title":"Nat Cancer"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.06.010","article-title":"Defining a cancer dependency map","volume":"170","author":"Tsherniak","year":"2017","journal-title":"Cell"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0623-z","article-title":"Functional genomic landscape of acute myeloid leukemia","volume":"562","author":"Tyner","year":"2018","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1301689","article-title":"Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia","volume":"368","year":"2013","journal-title":"N Engl J Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1158\/2643-3230.bcd-24-0342","article-title":"Single-cell transcriptional atlas of human hematopoiesis reveals genetic and hierarchy-based determinants of aberrant AML differentiation","volume":"6","author":"Zeng","year":"2025","journal-title":"Blood Cancer Discov"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1101\/gr.240663.118","article-title":"Benchmark and integration of resources for the estimation of human transcription factor activities","volume":"29","author":"Garcia-Alonso","year":"2019","journal-title":"Genome Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/mog2.70009","article-title":"Unraveling the underlying mechanisms of cancer stem cells in therapeutic resistance for optimizing treatment strategies","volume":"4","author":"Tan","year":"2025","journal-title":"MedComm Oncol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/s41375-018-0357-9","article-title":"Targeting FLT3 mutations in AML: review of current knowledge and evidence","volume":"33","author":"Daver","year":"2019","journal-title":"Leukemia"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1837940\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T04:45:42Z","timestamp":1779425142000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1837940\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,22]]},"references-count":17,"alternative-id":["10.3389\/fonc.2026.1837940"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1837940","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,22]]},"article-number":"1837940"}}