{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T08:49:12Z","timestamp":1791449352817,"version":"4.3.3"},"reference-count":25,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T00:00:00Z","timestamp":1787443200000},"content-version":"vor","delay-in-days":53,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"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\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2022R1C1C1003491"],"award-info":[{"award-number":["2022R1C1C1003491"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["iubmb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["BioFactors"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Hepatocellular carcinoma (HCC) is frequently complicated by bone metastasis, leading to severe skeletal\u2010related events. While alpha\u2010fetoprotein (AFP) is the gold\u2010standard biomarker for HCC diagnosis, its functional role as a systemic or paracrine mediator in the bone metastatic microenvironment remains largely unexplored. In the present study, we investigated whether HCC\u2010secreted AFP impairs bone formation by disrupting autophagic flux, the glycogen synthase kinase 3\u03b2 (GSK3\u03b2)\/\u03b2\u2010catenin signaling pathway, and Runt\u2010related transcription factor 2 (Runx2) stability in osteoblasts. Our results showed that AFP dose\u2010dependently inhibited osteoblast differentiation and mineralization. Mechanistically, AFP impaired autophagic flux, resulting in reduced phosphorylated GSK3\u03b2 (p\u2010GSK3\u03b2) and \u03b2\u2010catenin levels, which were accompanied by decreased Runx2 protein expression. Pharmacological activation of autophagy with rapamycin effectively reversed these AFP\u2010induced changes, restoring GSK3\u03b2\/\u03b2\u2010catenin signaling and Runx2 expression. Furthermore, using an ex\u00a0vivo mouse calvarial defect model, we found that HepG2\u2010derived AFP markedly impaired new bone regeneration and reduced the numbers of osteoblasts and osteocytes. Importantly, these effects were significantly attenuated by AFP silencing in HepG2 cells. Collectively, our findings identify HCC\u2010derived AFP as a potential mediator of bone impairment rather than solely a diagnostic biomarker. Targeting AFP\u2010mediated impairment of autophagic flux may represent a promising therapeutic strategy for mitigating skeletal complications and restoring bone homeostasis in patients with bone\u2010metastatic HCC.<\/jats:p>","DOI":"10.1002\/biof.70147","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T02:56:36Z","timestamp":1787540196000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>HCC<\/scp>\n                    \u2010Derived Alpha\u2010Fetoprotein Impairs Bone Regeneration by Impairing Autophagic Flux and Promoting Runx2 Degradation in Osteoblasts"],"prefix":"10.1002","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6504-1610","authenticated-orcid":false,"given":"Hyung\u2010Mun","family":"Yun","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial Pathology School of Dentistry, Kyung Hee University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung\u2010Ran","family":"Park","sequence":"additional","affiliation":[{"name":"Honam Regional Center Korea Basic Science Institute (KBSI)  Gwangju Republic of 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