{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T19:57:14Z","timestamp":1781812634358,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,17]]},"group-title":"Pathology","reference-count":77,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["NIDDK K01DK135793; P20GM113226; R01 AA010154, R01 DK077794, R56 DK134334"],"award-info":[{"award-number":["NIDDK K01DK135793; P20GM113226; R01 AA010154, R01 DK077794, R56 DK134334"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background &amp; Aims<\/jats:title>\n                  <jats:p>Systemic metabolic dysfunction promotes degenerative diseases in many organs, including liver and kidney. The liver is a master regulator of systemic metal ion homeostasis. Hepatic copper deficiency is increasingly observed in metabolic dysfunction associated steatotic liver disease (MASLD) and is associated with greater disease severity and poor outcomes. However, mechanisms linking copper dysregulation to MASLD and its co-morbidities remain poorly defined. We investigated whether impaired mitochondrial copper homeostasis contributes to MASLD-related pathobiology and represents a modifiable therapeutic axis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods &amp; Results<\/jats:title>\n                  <jats:p>\n                    Using dietary mouse models of MASLD and\n                    <jats:italic>in vitro<\/jats:italic>\n                    systems, we found that dietary copper deficiency induces lipotoxicity and suppresses mitochondrial metabolic programs. MASLD livers exhibited marked depletion of copper, impaired cytochrome c oxidase integrity, and bioenergetic failure. Targeted restoration of mitochondrial copper with the copper ionophore elesclomol normalized copper-handling programs, improved mitochondrial function, and suppressed ferroptotic stress, hepatocyte senescence, and fibroinflammatory remodeling. Mechanistically, reduced expression of the mitochondrial copper transporter\n                    <jats:italic>SLC25A3<\/jats:italic>\n                    and\n                    <jats:italic>MT-CO1<\/jats:italic>\n                    disrupted the SLC25A3\u2013SCO1\u2013MT-CO1\u2013CTR1 axis, limited copper uptake and destabilized copper-iron balance, promoting maladaptive cell fate changes. Across multiple human cohorts and mouse models, copper-iron imbalance tracks with MASLD progression, clinical outcomes, and multiple extrahepatic comorbidities; restoring copper homeostasis in mice with MASLD attenuates both liver and kidney inflammation and fibrosis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Mitochondrial copper deficiency is a mechanistically actionable driver of MASLD that promotes bioenergetic failure, ferroptosis, senescence and fibroinflammatory damage in the liver and other organs. Targeting copper-centered mitochondrial regulation represents a novel biomarker and therapeutic strategy for MASLD and its systemic complications.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.15.731916","type":"posted-content","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T09:55:19Z","timestamp":1781690119000},"source":"Crossref","is-referenced-by-count":0,"title":["Disrupted Mitochondrial Copper Homeostasis Promotes Ferroptotic Stress, Senescence and MASLD Progression"],"prefix":"10.64898","author":[{"given":"Niansheng","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Medicine, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuyang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University, Durham, NC 27710, USA"},{"name":"Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh K.","family":"Dutta","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Umbaugh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaojuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seh Hoon","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0113-5981","authenticated-orcid":false,"given":"Dennis C.","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville, Louisville, KY 40202, USA"},{"name":"Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Mae","family":"Diehl","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuo","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University, Durham, NC 27710, USA"},{"name":"Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061812450770000_2026.06.15.731916v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2020.101138"},{"key":"2026061812450770000_2026.06.15.731916v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c130024"},{"key":"2026061812450770000_2026.06.15.731916v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-025-00599-1"},{"key":"2026061812450770000_2026.06.15.731916v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2025.08.003"},{"key":"2026061812450770000_2026.06.15.731916v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2011.08.016"},{"key":"2026061812450770000_2026.06.15.731916v1.6","doi-asserted-by":"publisher","DOI":"10.14309\/ajg.0000000000003379"},{"key":"2026061812450770000_2026.06.15.731916v1.7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8137.2009.02846.x"},{"key":"2026061812450770000_2026.06.15.731916v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.724"},{"key":"2026061812450770000_2026.06.15.731916v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2021.129979"},{"key":"2026061812450770000_2026.06.15.731916v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cvsm.2009.02.001"},{"key":"2026061812450770000_2026.06.15.731916v1.11","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/88.3.851S"},{"key":"2026061812450770000_2026.06.15.731916v1.12","doi-asserted-by":"publisher","DOI":"10.1097\/CM9.0000000000002697"},{"key":"2026061812450770000_2026.06.15.731916v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/ajg.2010.170"},{"key":"2026061812450770000_2026.06.15.731916v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtemb.2011.08.146"},{"key":"2026061812450770000_2026.06.15.731916v1.15","doi-asserted-by":"publisher","DOI":"10.1002\/iub.1613"},{"key":"2026061812450770000_2026.06.15.731916v1.16","doi-asserted-by":"publisher","DOI":"10.3390\/nu10111815"},{"key":"2026061812450770000_2026.06.15.731916v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.05.030"},{"key":"2026061812450770000_2026.06.15.731916v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2015.04.009"},{"key":"2026061812450770000_2026.06.15.731916v1.19","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1393"},{"key":"2026061812450770000_2026.06.15.731916v1.20","doi-asserted-by":"publisher","DOI":"10.7570\/jomes23054"},{"key":"2026061812450770000_2026.06.15.731916v1.21","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23137280"},{"key":"2026061812450770000_2026.06.15.731916v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.02.004"},{"key":"2026061812450770000_2026.06.15.731916v1.23","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.04.007"},{"key":"2026061812450770000_2026.06.15.731916v1.24","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c170045"},{"key":"2026061812450770000_2026.06.15.731916v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-024-00652-w"},{"key":"2026061812450770000_2026.06.15.731916v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/icb.1973.15"},{"key":"2026061812450770000_2026.06.15.731916v1.27","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2002.tb00452.x"},{"key":"2026061812450770000_2026.06.15.731916v1.28","doi-asserted-by":"publisher","DOI":"10.1111\/liv.15711"},{"key":"2026061812450770000_2026.06.15.731916v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2017.08.055"},{"key":"2026061812450770000_2026.06.15.731916v1.30","doi-asserted-by":"publisher","DOI":"10.1002\/iub.50"},{"key":"2026061812450770000_2026.06.15.731916v1.31","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh197"},{"key":"2026061812450770000_2026.06.15.731916v1.32","doi-asserted-by":"publisher","DOI":"10.1039\/C7MT00221A"},{"key":"2026061812450770000_2026.06.15.731916v1.33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1806296115"},{"key":"2026061812450770000_2026.06.15.731916v1.34","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2216722120"},{"key":"2026061812450770000_2026.06.15.731916v1.35","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz8899"},{"key":"2026061812450770000_2026.06.15.731916v1.36","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-022-02485-0"},{"key":"2026061812450770000_2026.06.15.731916v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2020.108701"},{"key":"2026061812450770000_2026.06.15.731916v1.38","doi-asserted-by":"publisher","DOI":"10.2147\/DMSO.S346648"},{"key":"2026061812450770000_2026.06.15.731916v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111498"},{"key":"2026061812450770000_2026.06.15.731916v1.40","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.000265"},{"key":"2026061812450770000_2026.06.15.731916v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2024.06.008"},{"key":"2026061812450770000_2026.06.15.731916v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2013.01.018"},{"key":"2026061812450770000_2026.06.15.731916v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.01.019"},{"key":"2026061812450770000_2026.06.15.731916v1.44","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx344"},{"key":"2026061812450770000_2026.06.15.731916v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.12.001"},{"key":"2026061812450770000_2026.06.15.731916v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2017.08.015"},{"key":"2026061812450770000_2026.06.15.731916v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-021-00483-8"},{"key":"2026061812450770000_2026.06.15.731916v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-024-00654-8"},{"key":"2026061812450770000_2026.06.15.731916v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-024-01520-w"},{"key":"2026061812450770000_2026.06.15.731916v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2025.08.021"},{"key":"2026061812450770000_2026.06.15.731916v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-57616-w"},{"key":"2026061812450770000_2026.06.15.731916v1.52","doi-asserted-by":"publisher","DOI":"10.1172\/JCI180310"},{"key":"2026061812450770000_2026.06.15.731916v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32552-1"},{"key":"2026061812450770000_2026.06.15.731916v1.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2022.11.001"},{"key":"2026061812450770000_2026.06.15.731916v1.55","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-023-00928-2"},{"key":"2026061812450770000_2026.06.15.731916v1.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2015.03.067"},{"key":"2026061812450770000_2026.06.15.731916v1.57","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2098"},{"key":"2026061812450770000_2026.06.15.731916v1.58","doi-asserted-by":"publisher","DOI":"10.1136\/openhrt-2018-000784"},{"key":"2026061812450770000_2026.06.15.731916v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajo.2008.08.014"},{"key":"2026061812450770000_2026.06.15.731916v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2024.107139"},{"key":"2026061812450770000_2026.06.15.731916v1.61","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-015-9721-x"},{"key":"2026061812450770000_2026.06.15.731916v1.62","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0161033"},{"key":"2026061812450770000_2026.06.15.731916v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2018.05.006"},{"key":"2026061812450770000_2026.06.15.731916v1.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2025.08.021"},{"key":"2026061812450770000_2026.06.15.731916v1.65","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-014-9708-5"},{"key":"2026061812450770000_2026.06.15.731916v1.66","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.470674"},{"key":"2026061812450770000_2026.06.15.731916v1.67","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.856300"},{"key":"2026061812450770000_2026.06.15.731916v1.68","doi-asserted-by":"publisher","DOI":"10.1172\/JCI193107"},{"key":"2026061812450770000_2026.06.15.731916v1.69","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2015.10.016"},{"key":"2026061812450770000_2026.06.15.731916v1.70","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty560"},{"key":"2026061812450770000_2026.06.15.731916v1.71","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"2026061812450770000_2026.06.15.731916v1.72","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2026061812450770000_2026.06.15.731916v1.73","doi-asserted-by":"publisher","DOI":"10.1016\/j.xinn.2021.100141"},{"key":"2026061812450770000_2026.06.15.731916v1.74","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01796-1"},{"key":"2026061812450770000_2026.06.15.731916v1.75","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0351-9"},{"key":"2026061812450770000_2026.06.15.731916v1.76","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01767-y"},{"key":"2026061812450770000_2026.06.15.731916v1.77","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4463"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.15.731916","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T19:45:15Z","timestamp":1781811915000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.15.731916"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":77,"URL":"https:\/\/doi.org\/10.64898\/2026.06.15.731916","relation":{},"subject":[],"published":{"date-parts":[[2026,6,17]]},"subtype":"preprint"}}