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Ubiquitin (Ub), a short polypeptide predominantly involved in proteasome\u2010mediated protein degradation, has been detected extracellularly in body fluids. In certain diseases, it exerts immune\u2010regulatory functions, including the modulation of macrophage polarization. Nevertheless, its immune\u2010regulatory role in multiple myeloma (MM) remains undetermined. This study investigated the role of extracellular ubiquitin (eUb) in macrophage polarization and MM progression. We demonstrated that serum eUb levels were significantly higher in MM patients than in healthy volunteers. Elevated eUb levels were closely associated with a poor prognosis in MM patients. Exposure to eUb induced M2 macrophage polarization, which in turn promoted MM cell proliferation and EMT via the CXCR4\/JAK1\/STAT3 pathway. Notably, STAT3 was identified as a transcription factor that directly binds to the CXCR4 promoter, enhancing its expression and establishing a positive\u2010feedback loop. Collectively, eUb promotes MM cell proliferation and EMT\u2010like changes by driving M2 macrophage polarization through activation of the CXCR4\/JAK1\/STAT3 positive\u2010feedback pathway. These findings underscore the pathological significance of eUb in the MM tumor microenvironment and suggest that targeting this pathway may provide novel therapeutic strategies for MM.<\/jats:p>","DOI":"10.1002\/jcb.70073","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T11:41:05Z","timestamp":1762947665000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Extracellular Ubiquitin Drives M2 Macrophage Polarization in Multiple Myeloma Through JAK1\/STAT3\u2010mediated Transcriptional Activation of CXCR4"],"prefix":"10.1002","volume":"126","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9670-398X","authenticated-orcid":false,"given":"Xi","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Hematology, Myeloma &amp; Lymphoma Center, Shanghai Changzheng Hospital Navy Medical University Shanghai 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