{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T06:02:15Z","timestamp":1784959335294,"version":"3.55.0"},"reference-count":45,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T00:00:00Z","timestamp":1783814400000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373891"],"award-info":[{"award-number":["82373891"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Transferrin receptor 1 (TfR\u20101), a key mediator of cellular iron uptake, is significantly upregulated across a broad spectrum of malignancies, and its overexpression highly correlated with poor clinical outcomes, such as in breast cancer. However, its precise role in breast cancer progression remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated clinical breast cancer tissue specimens and public transcriptomic datasets to analyse the clinical correlation between TfR\u20101 expression and tumour metastasis. A series of in vitro cell functional assays and in vivo xenograft tumour metastasis models were performed to validate the regulatory effect of TfR\u20101 on breast cancer proliferation and metastasis. Co\u2011immunoprecipitation, phosphorylation detection and protein stability assays were further applied to dissect the intermolecular regulatory network among TfR\u20101, Hematopoietic Cell Kinase (HCK) and Ubiquitin Specific Peptidase 32 (USP32).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Clinical data analysis revealed that elevated TfR\u20101 expression was tightly linked to metastatic phenotype in breast cancer. Functional experiments confirmed that upregulated TfR\u20101 robustly boosted the proliferative and metastatic capacity of breast cancer cells in vitro and in vivo. Mechanistically, TfR\u20101 dual\u2011regulates HCK, it directly induces HCK phosphorylation, while simultaneously activating USP32 to block HCK protein degradation and sustain HCK abundance. Activated HCK further triggers STAT3 transcription factor signalling, which drives the upregulation and secretion of matrix metalloproteinase 9 (MMP9). In addition, HCK reciprocally phosphorylates TfR\u20101 to establish a positive feedback circuit amplifying the prometastatic signalling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This work identifies a previously uncharacterized prometastatic function of TfR\u20101 independent of its canonical iron transport activity in breast cancer. We uncover a reciprocal TfR\u20111\/HCK positive feedback axis that activates the USP32\u2011HCK\u2011STAT3\u2011MMP9 signalling cascade to facilitate breast cancer metastasis, which provides novel candidate therapeutic targets for metastatic breast cancer intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70731","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T03:32:28Z","timestamp":1783913548000},"source":"Crossref","is-referenced-by-count":0,"title":["Non\u2010canonical function of transferrin receptor\u20101 promotes breast cancer metastasis by activating HCK\u2012STAT3\u2012MMP9 signalling"],"prefix":"10.1002","volume":"16","author":[{"given":"Qing","family":"Zhao","sequence":"first","affiliation":[{"name":"Nanchang University School of Pharmacy Nanchang University  Nanchang PR China"},{"name":"State Key Laboratory of Drug Research Division of Antitumor Pharmacology Shanghai Institute of Materia Medica, Chinese 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