{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T21:04:09Z","timestamp":1790370249243,"version":"4.1.0"},"reference-count":64,"publisher":"Wiley","issue":"29","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DK119202"],"award-info":[{"award-number":["R01DK119202"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DK128823"],"award-info":[{"award-number":["R01DK128823"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Metastatic recurrence is the principal cause of cancer mortality. Pancreatic ductal adenocarcinoma (PDAC) and triple\u2010negative breast cancer (TNBC) recur frequently after apparently curative therapy. Carbon monoxide (CO) is an endogenously produced signaling molecule with cytoprotective properties, but clinical use of CO gas is constrained by safety and dose\u2010control challenges. Here, a metal\u2010free CO prodrug (\n                    <jats:bold>CO\u2010116<\/jats:bold>\n                    ) suppresses metastatic progression in vivo. In experimental models of PDAC and TNBC,\n                    <jats:bold>CO\u2010116<\/jats:bold>\n                    reduces metastatic burden without evidence of overt toxicity while maintaining carboxyhemoglobin within physiological ranges. At an equivalent total weekly dose, dividing the dose into more frequent, lower administrations achieves greater efficacy than a single weekly dose, indicating schedule dependence. Mechanistically,\n                    <jats:bold>CO\u2010116<\/jats:bold>\n                    downregulates the heme importer HRG1 and attenuates a downstream CYP1B1\u2013SP1 program; gain\u2010 and loss\u2010of\u2010function studies establish HRG1 as a functional mediator of metastatic progression and CO responsiveness. An independent cohort using a distinct metal\u2010free scaffold (\n                    <jats:bold>CO\u2010103<\/jats:bold>\n                    ) likewise reduces metastasis in PDAC, supporting a scaffold\u2010independent class effect. These findings establish a mechanistically anchored, non\u2010inhaled CO strategy to suppress metastasis and motivate adjuvant development focused on schedule optimization and biomarker\u2010guided dosing.\n                  <\/jats:p>","DOI":"10.1002\/advs.202519898","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T18:43:22Z","timestamp":1774032202000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Metal\u2010Free Carbon Monoxide Prodrug Suppresses Metastasis of Pancreatic and Breast Cancer"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0251-1819","authenticated-orcid":false,"given":"Tiantian","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Weill Cornell Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5473-1026","authenticated-orcid":false,"given":"Xiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Weill Cornell Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Chemistry Center for Diagnostics and Therapeutics Georgia State University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muskan","family":"Gori","sequence":"additional","affiliation":[{"name":"Department of Chemistry Center for Diagnostics and Therapeutics Georgia State University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit Kumar","family":"Varshnaya","sequence":"additional","affiliation":[{"name":"Department of Chemistry Center for Diagnostics and Therapeutics Georgia State University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongning","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Chemistry Center for Diagnostics and Therapeutics Georgia State University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0354-8034","authenticated-orcid":false,"given":"Cheryl","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Weill Cornell Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4379-4089","authenticated-orcid":false,"given":"Michelle Yi Qin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Weill Cornell Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9437-6452","authenticated-orcid":false,"given":"Zhengming","family":"Chen","sequence":"additional","affiliation":[{"name":"Biostatistics Division Department of Population Health Sciences Weill Cornell Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4834-6401","authenticated-orcid":false,"given":"George","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Weill Cornell Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5916-8106","authenticated-orcid":false,"given":"Erika","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Weill Cornell Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2834-5890","authenticated-orcid":false,"given":"Qiyue","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Chemistry Center for Diagnostics and Therapeutics Georgia State University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tan A.","family":"Ince","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Weill Cornell Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7489-7699","authenticated-orcid":false,"given":"Chalet","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2200-5270","authenticated-orcid":false,"given":"Binghe","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry Center for Diagnostics and Therapeutics Georgia State University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0917-0853","authenticated-orcid":false,"given":"Yi\u2010Chieh Nancy","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Weill Cornell Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v17.i9.1126"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0000000000004093"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.695627"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.5306\/wjco.v12.i3.164"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781119783435"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0954\u20106820.1967.tb12633.x"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7678352"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2010.07.011"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c00823"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557\u2010018\u20100055\u20102"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.22116"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00469.2024"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.100677"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00286.2023"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.14.11.1305"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.4103\/2045\u20109912.184719"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1716747115"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2022.115016"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abl4135"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202308346"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ultsonch.2020.105427"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201541601"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204\u2010015\u20101579\u20105"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867053764635"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1039\/d3sc00411b"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2023.115642"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986711796504583"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja108820s"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1039\/c4dt02966f"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2018.06.008"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10060915"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21082970"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11239\u2010019\u201001980\u20100"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21062082"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1039\/c4cc07748b"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.8b00019"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c01056"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20220254"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10060915"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11239\u2010019\u201001980\u20100"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21082970"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2012.04.026"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja108820s"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1039\/d2ob01076c"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1039\/c7sc01647f"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2013.12.007"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201013\u20101075"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.215831"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201700936"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201608732"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201608732"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2020.07.040"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1556\u20104029.2006.00212.x"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1203\/00006450\u2010199904020\u201000405"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2021.08.059"},{"key":"e_1_2_9_57_1","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/9781119783435.ch17","volume-title":"Carbon Monoxide in Drug Discovery: Basics, Pharmacology, and Therapeutic Potential","author":"De L. C.","year":"2022"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1124\/pharmrev.121.000564"},{"issue":"2","key":"e_1_2_9_59_1","first-page":"657","article-title":"Group UCCPS. Symptoms of Carbon Monoxide Poisoning Do Not Correlate With the Initial Carboxyhemoglobin Level","volume":"39","author":"Hampson N. B.","year":"2012","journal-title":"Undersea & Hyperbaric Medicine: Journal of the Undersea and Hyperbaric Medical Society, Inc"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03799"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.017830"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.063248"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20104939\u20108879\u20102_27"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.217240"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.2c07504"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202519898","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.202519898","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202519898","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T20:38:42Z","timestamp":1790368722000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202519898"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,20]]},"references-count":64,"journal-issue":{"issue":"29","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1002\/advs.202519898"],"URL":"https:\/\/doi.org\/10.1002\/advs.202519898","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,20]]},"assertion":[{"value":"2025-10-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e19898"}}