{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:25:06Z","timestamp":1787030706631,"version":"build-2736575974"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Myeloma bone disease (MBD) is driven by excessive osteoclast activation and progressive bone destruction, but the role of exosomal circular RNAs (circRNAs) from myeloma cells remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Exosomes from U266 and MM1S cells were isolated and used to treat THP-1 cells. Osteoclast differentiation was assessed by TRAP staining and bone resorption assay. circRNA sequencing of U266 exosomes and MBD patient blood was performed to identify overlapping circRNAs. A ceRNA network was constructed using circBank and miRTarBase, combined with single-cell RNA-seq (GSE271107) to prioritize candidate target genes. Functional experiments included circ_0002724 knockdown\/overexpression in U266 cells, exosomal transfer, TRAP, bone resorption, qRT-PCR, RNA-FISH\/IF, dual-luciferase reporter assay, and immunohistochemistry of patient bone marrow biopsies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>U266-derived exosomes exhibited stronger osteoclast-inducing activity than MM1S-derived exosomes. Intersection analysis identified 14 common circRNAs, among which circ_0002724 showed the highest predicted miRNA-binding capacity and was significantly upregulated in THP-1 cells after exosome treatment. A circ_0002724-associated regulatory network identified miR-4753-3p, IFIT1, and RANK as potential downstream components. Single-cell analysis revealed that IFIT1 was highly expressed in MM osteoclast precursor cells and increased during osteoclast differentiation. Exosomal circ_0002724 was internalized by THP-1 cells; circ_0002724 knockdown reduced, whereas overexpression enhanced, TRAP-positive osteoclast formation and bone resorption activity, accompanied by altered RANK and IFIT1 expression. Dual-luciferase reporter assays supported the interactions between circ_0002724, miR-4753-3p, RANK, and IFIT1. Immunohistochemical analysis of patient biopsies demonstrated positive associations of circ_0002724, RANK, and IFIT1 with MBD severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Myeloma-derived exosomal circ_0002724 promotes osteoclast activation and bone resorption and is associated with regulation of the miR-4753-3p\/IFIT1\/RANK network. These findings provide new insights into exosome-mediated tumor\u2013bone microenvironment communication and suggest circ_0002724 as a potential biomarker and candidate therapeutic target for MBD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1887386","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:28:38Z","timestamp":1787027318000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Myeloma-derived exosomal circ_0002724 promotes osteoclastogenesis through a miR-4753-3p\/IFIT1 and RANK axis in myeloma bone disease"],"prefix":"10.3389","volume":"16","author":[{"given":"Nayan","family":"Yi","sequence":"first","affiliation":[{"name":"The First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine","place":["Jinan, 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