{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:52:42Z","timestamp":1791298362301,"version":"4.1.0"},"posted":{"date-parts":[[2026,10,1]]},"group-title":"Cancer Biology","reference-count":38,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01 CA298818"],"award-info":[{"award-number":["R01 CA298818"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 CA257811"],"award-info":[{"award-number":["R01 CA257811"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R56 EB030512"],"award-info":[{"award-number":["R56 EB030512"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Pro CA08748"],"award-info":[{"award-number":["Pro CA08748"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Ferroptosis has attracted significant attention for its potential to treat drug resistant tumors, along with its role in neurodegeneration and ischemia. Several ferroptosis targets were identified in the past decade, yet it is also highly affected by cellular metabolism and epithelial or mesenchymal phenotypes which limits the utility of these targets across diverse cell and tissue types. To address this, we utilized chemo-resistant cancer cell lines with different metastatic potential and tissue origins and discovered a common role of cytoplasmic ion changes during ferroptosis. We observed significant changes in intracellular potassium, sodium and chloride levels upon induction of ferroptosis. Therefore, we screened several ion channel inhibitors and activators (i.e. modulators) and identified Kv7.2 and CFTR modulators influence ferroptosis execution despite the fact that these cell lines do not express these proteins. We demonstrated that clinically approved modulators of CFTR and Kv7.2 can inhibit ferroptosis which indicates that these inhibitors could be repurposed as treatments in ferroptosis-associated diseases such as neurodegeneration and kidney diseases independent of ion channel expression. These modulators also influenced potassium and chloride levels in different contexts indicating off-target effects may also lead to changes in ion levels and may serve as a ferroptosis target. Further, we demonstrated that sustained imbalance of sodium, potassium and chloride ions with ferroptosis inducer salinomycin and digoxin, a Na\n                  <jats:sup>+<\/jats:sup>\n                  \/K\n                  <jats:sup>+<\/jats:sup>\n                  ATPase inhibitor, enhanced ferroptosis. The combination of salinomycin and digoxin successfully enhanced ferroptotic cell death across both cell lines with different metabolic signatures in vitro, offering a novel ferroptosis target. This combination significantly reduced tumor growth in vivo compared with the single agent alone, offering a new therapeutic modality against drug resistant tumors.\n                <\/jats:p>","DOI":"10.64898\/2026.09.30.755323","type":"posted-content","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T11:45:15Z","timestamp":1790855115000},"source":"Crossref","is-referenced-by-count":0,"title":["Sustained Ion Imbalances Enhance Ferroptosis"],"prefix":"10.64898","author":[{"given":"Ali Yasin","family":"Sonay","sequence":"first","affiliation":[{"name":"Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center; New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elana","family":"Apfelbaum","sequence":"additional","affiliation":[{"name":"Pharmacology Program, Weill Cornell Medical College; New York, NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nermin","family":"Mostafa","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center; New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5282-9385","authenticated-orcid":false,"given":"Jan","family":"Grimm","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"name":"Pharmacology Program, Weill Cornell Medical College; New York, NY USA"},{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"name":"Department of Radiology, Weill, Cornell Medical Center; New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100607050980000_2026.09.30.755323v1.1","doi-asserted-by":"crossref","unstructured":"Fujihara, K. 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