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To address this challenge, identifying novel therapeutic target combinations is critical for improving metastatic breast cancer treatment. This study investigates the mechanism by which asparaginyl endopeptidase (AEP) regulates breast cancer metastasis. Bioinformatics analysis revealed a potential interaction between AEP and CD74, which was subsequently confirmed through co\u2010immunoprecipitation (co\u2010IP) experiments. Further investigations demonstrated that AEP activates ERK pathway phosphorylation via CD74 regulation, thereby enhancing epithelial\u2010mesenchymal transition (EMT) progression and promoting breast cancer cell migration. Compared to controls, dual inhibition of AEP and CD74 effectively reduced EMT markers and the migratory capacity of cancer cells in\u00a0vitro. Subsequent in\u00a0vivo experiments showed that this combinatorial strategy significantly suppressed breast cancer lung metastasis in mice without observable toxicity. These findings elucidate the molecular mechanism through which AEP promotes metastasis via CD74 regulation, while validating the therapeutic efficacy and safety of dual AEP\/CD74 targeting. This study provides a novel conceptual framework and potential therapeutic targets for metastatic breast cancer intervention.<\/jats:p>","DOI":"10.1111\/jcmm.70616","type":"journal-article","created":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T09:26:28Z","timestamp":1748078788000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Combination of <scp>MIF<\/scp> Inhibitor and <scp>AEP<\/scp> Targeted Inhibitor to Reduce Lung Metastasis in Breast Cancer and Its Mechanism"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1720-0802","authenticated-orcid":false,"given":"Junsong","family":"Chen","sequence":"first","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University  Shanghai 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