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Treatment options for OS have remained largely unchanged for decades, consisting primarily of cytotoxic chemotherapy and surgery, thus necessitating the urgent need for novel therapies. Tropolones are naturally occurring seven\u2010membered non\u2010benzenoid aromatic compounds that possess antiproliferative effects in a wide array of cancer cell types. MO\u2010OH\u2010Nap is an \u03b1\u2010substituted tropolone that has activity as an iron chelator. Here, we demonstrate that MO\u2010OH\u2010Nap activates all three arms of the unfolded protein response (UPR) pathway and induces apoptosis in a panel of human OS cell lines. Co\u2010incubation with ferric chloride or ammonium ferrous sulfate completely prevents the induction of apoptotic and UPR markers in MO\u2010OH\u2010Nap\u2010treated OS cells. MO\u2010OH\u2010Nap upregulates transferrin receptor 1 (TFR1) protein levels, as well as TFR1, divalent metal transporter 1 (DMT1), iron\u2010regulatory proteins (IRP1, IRP2), ferroportin (FPN), and zinc transporter 14 (ZIP14) transcript levels, demonstrating the impact of MO\u2010OH\u2010Nap on iron\u2010homeostasis pathways in OS cells. Furthermore, MO\u2010OH\u2010Nap treatment restricts the migration and invasion of OS cells in vitro. Lastly, metabolomic profiling of MO\u2010OH\u2010Nap\u2010treated OS cells revealed distinct changes in purine and pyrimidine metabolism. Collectively, we demonstrate that MO\u2010OH\u2010Nap\u2010induced cytotoxic effects in OS cells are dependent on the tropolone's ability to alter cellular iron availability and that this agent exploits key metabolic pathways. These studies support further evaluation of MO\u2010OH\u2010Nap as a novel treatment for OS.<\/jats:p>","DOI":"10.1002\/ddr.22129","type":"journal-article","created":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T03:55:18Z","timestamp":1699934118000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Investigation of the activity of a novel tropolone in osteosarcoma"],"prefix":"10.1002","volume":"85","author":[{"given":"Staci L.","family":"Haney","sequence":"first","affiliation":[{"name":"Department of Internal Medicine University of Nebraska Medical Center Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of Nebraska Medical Center Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sai 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