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The role of synovial macrophages in OA pathogenesis remains incompletely understood, and the molecular mechanisms by which they drive cartilage destruction have not been fully elucidated. By integrating human OA microarrays, synovial single\u2010cell RNA\u2010seq, and multi\u2010level validation, we identified lymphocyte\u2010specific protein 1 (LSP1) as a macrophage\u2010specific hub gene upregulated in OA. Mechanistically, LSP1 directly binds to and inhibits superoxide dismutase 1 (SOD1), inducing a redox imbalance that concurrently activates the NADPH oxidase (NOX) and mitochondrial reactive oxygen species (mtROS) pathways. This cascade drives the release of macrophage extracellular traps (METs), which directly damage chondrocytes and accelerate OA progression. Virtual screening of the DrugBank database identified the cardiac glycoside digoxin as a compound that competitively binds LSP1, restores SOD1 activity, and suppresses the NOX\/mtROS\u2010METs axis. This study defines a novel LSP1\u2010SOD1\u2010METs pathogenic axis in OA and nominates digoxin as a repurposable therapeutic candidate. Unlike its previously reported cartilage\u2010targeting mechanism, digoxin alleviates OA by suppressing synovial inflammation via LSP1 targeting, highlighting its dual\u2010target potential for concurrent modulation of synovial and cartilage pathology.<\/jats:p>","DOI":"10.1002\/advs.78097","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:51:08Z","timestamp":1790779868000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Digoxin Alleviates Osteoarthritis by Inhibiting Macrophage Extracellular Trap Formation via Disruption of the LSP1\u2010SOD1 Interaction"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3039-3822","authenticated-orcid":false,"given":"Yankai","family":"Pan","sequence":"first","affiliation":[{"name":"Department of Joint Bone Disease Surgery Changhai Hospital Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7072-095X","authenticated-orcid":false,"given":"Xinzhe","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Joint Bone Disease Surgery Changhai Hospital Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7181-8032","authenticated-orcid":false,"given":"Chuanju","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Rehabilitation Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3445-8210","authenticated-orcid":false,"given":"Jianfei","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Joint Bone Disease Surgery Changhai Hospital Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Joint Bone Disease Surgery Changhai Hospital Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Joint Bone Disease Surgery Changhai Hospital Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Joint Bone Disease Surgery Changhai Hospital Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Joint Bone Disease Surgery Changhai Hospital Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0841-4750","authenticated-orcid":false,"given":"Yihong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Joint Bone Disease Surgery Changhai Hospital Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6477-9461","authenticated-orcid":false,"given":"Weidong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Joint Bone Disease Surgery Changhai Hospital Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2016.148"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572\u2010025\u201000594\u20106"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2016.136"},{"issue":"2","key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1136\/annrheumdis-2014-206295","article-title":"Oxidative Changes and Signalling Pathways are Pivotal in Initiating Age\u2010Related Changes in Articular Cartilage","volume":"75","author":"Hui W.","year":"2016","journal-title":"Annals of the Rheumatic Diseases"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2015.01.008"},{"issue":"2","key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s10067-019-04768-y","article-title":"Alterations in Peripheral T Cell and B Cell Subsets in Patients With Osteoarthritis","volume":"39","author":"Zhu W.","year":"2020","journal-title":"Clinical Rheumatology"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.210285"},{"issue":"2","key":"e_1_2_11_9_1","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.125325","article-title":"Macrophage Proliferation Distinguishes 2 Subgroups of Knee Osteoarthritis Patients","volume":"4","author":"Wood M. 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