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Although VEN resistance has been linked to Mcl-1 upregulation, thereby switching survival dependence from Bcl-2 to Mcl-1, the mechanism underlying increased Mcl-1 expression remains elusive. Given that changes in cellular redox state affect cancer cell fate, we investigated the crosstalk between intracellular redox milieu and Mcl-1 upregulation in VEN-resistant cells. Results show that increased Mcl-1 protein levels in VEN-resistant hematologic malignant cells are associated with elevated intracellular superoxide (O<jats:sub>2<\/jats:sub>\n            <jats:sup>.\u2212<\/jats:sup>) levels. Validating that, augmenting intracellular O<jats:sub>2<\/jats:sub>\n            <jats:sup>.\u2212<\/jats:sup> in VEN-sensitive cells increases Mcl-1 phosphorylation at threonine-163 (T163pMcl-1) and protein stability via reduced Mcl-1 ubiquitination and degradation. Furthermore, redox-activated AKT\/PKB is implicated in O<jats:sub>2<\/jats:sub>\n            <jats:sup>.\u2212<\/jats:sup>-induced T163pMcl-1, as reducing intracellular O<jats:sub>2<\/jats:sub>\n            <jats:sup>.\u2212<\/jats:sup> or inhibiting AKT significantly decreases T163pMcl-1 and Mcl-1 accumulation, which amplifies mitochondrial apoptotic priming and restores VEN sensitivity. Importantly, combination therapy with AKT inhibitor, capivasertib, and VEN reduced VEN-resistant cells systemically and prolonged survival in a murine model. Collectively, a novel redox-dependent mechanism of Mcl-1 stability is demonstrated for the acquisition of VEN resistance, which has therapeutic implications for employing redox modulating strategies and AKT inhibitors against VEN-resistant hematologic malignancies.<\/jats:p>","DOI":"10.1038\/s41375-025-02694-4","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T07:58:35Z","timestamp":1753343915000},"page":"2477-2491","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Superoxide-mediated phosphorylation and stabilization of Mcl-1 by AKT underlie venetoclax resistance in hematologic malignancies"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9188-7131","authenticated-orcid":false,"given":"Stephen J. F.","family":"Chong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolin X. 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CJ Wu holds equity in BioNTech, and receives research funding from Pharmacyclics. R. Gui\u00e8ze has received travel and research funding, and honoraria for consulting from Johnson and Johnson, AbbVie, BeOne Medicine, AstraZeneca, Eli Lilly, Amgen, and Roche. All other authors have no disclosures of conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All experimental methods in this study were performed in accordance with the relevant guidelines and regulations. Patient samples were obtained following informed consent and approval by relevant institutional review board (IRB). Lymphoma patient samples were obtained from National University Hospital (NUH), Singapore (IRB-#2012\/00579) and CLL patient samples were obtained from DFCI, Boston, USA (IRB-#17-561). All experiments pertaining to animal study were approved by the SingHealth experimental medicine centre (SEMC) institutional animal care and use committee (IACUC-#1681).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}