{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:54:20Z","timestamp":1785772460821,"version":"3.56.0"},"reference-count":27,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100005047","name":"Natural Science Foundation of Liaoning Province","doi-asserted-by":"publisher","award":["2022\u2010MS\u2010216"],"award-info":[{"award-number":["2022\u2010MS\u2010216"]}],"id":[{"id":"10.13039\/501100005047","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Osteosarcoma (OS) is a primary bone malignancy, and its progression can be hindered by inducing programmed cell death (PCD). Protein disulfide\u2010isomerase (PDI) regulates cancer cell death; however, its functional role in OS remains unclear.\n                    <jats:italic>P4HB<\/jats:italic>\n                    expression was assessed in tumor tissues and cells from patients with OS using RT\u2010qPCR. The effects of\n                    <jats:italic>P4HB<\/jats:italic>\n                    on OS cell lines were evaluated. Western blotting was used to assess the impact of P4HB on various forms of PCD (apoptosis, ferroptosis, and pyroptosis). Bioinformatics analysis identified the upstream and downstream mechanisms of\n                    <jats:italic>P4HB<\/jats:italic>\n                    in OS progression. A xenograft tumorigenesis study was performed to elucidate the role and mechanism of\n                    <jats:italic>P4HB<\/jats:italic>\n                    in OS progression. Elevated\n                    <jats:italic>P4HB<\/jats:italic>\n                    expression was observed in OS tissue samples and cell lines. Downregulation of\n                    <jats:italic>P4HB<\/jats:italic>\n                    suppressed OS cell growth, migration, and invasiveness and induced PCD. Functional enrichment analysis and experimental validation revealed that PDI upregulated vascular endothelial growth factor A (VEGFA) vascular endothelial growth factor receptor 2 (VEGFR2) signaling. Methylation analysis showed that the m6A demethylase fat mass and obesity\u2010associated protein (FTO) decreased\n                    <jats:italic>P4HB<\/jats:italic>\n                    m6A levels and enhanced VEGFA\u2013VEGFR2 signaling in OS cells. Moreover,\n                    <jats:italic>FTO<\/jats:italic>\n                    overexpression enhanced the proliferative, migratory, and invasive capabilities of OS cells and decreased PCD. Finally,\n                    <jats:italic>FTO<\/jats:italic>\n                    knockdown inhibited tumor growth and lung metastasis of OS by decreasing the activity of the PDI\/VEGFA\u2013VEGFR2 signaling axis. Mechanistically,\n                    <jats:italic>FTO<\/jats:italic>\n                    \u2010mediated m6A modification of\n                    <jats:italic>P4HB<\/jats:italic>\n                    regulates PCD in OS through activation of this axis. \u00a9 2026 The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70083","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T11:08:09Z","timestamp":1780657689000},"page":"69-82","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>FTO<\/scp>\n                    \u2010mediated\n                    <scp>m6A<\/scp>\n                    modification of protein disulfide\u2010isomerase activates\n                    <scp>VEGFA<\/scp>\n                    \u2013\n                    <scp>VEGFR2<\/scp>\n                    to suppress programmed cell death in osteosarcoma"],"prefix":"10.1002","volume":"270","author":[{"given":"Jiashi","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopedics Shengjing Hospital of China Medical University  Shenyang PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Shengjing Hospital of China Medical University  Shenyang PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"He","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Shengjing Hospital of China Medical University  Shenyang PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9967-1477","authenticated-orcid":false,"given":"Weizheng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pediatric Orthopaedics Shengjing Hospital of China Medical University  Shenyang PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2020.12.024"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-023-04614-4"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-022-00409-y"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-022-01735-y"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.847345"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.33787"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/15384047.2019.1680061"},{"key":"e_1_2_9_9_1","article-title":"Baicalin induces ferroptosis in osteosarcomas through a novel Nrf2\/xCT\/GPX4 regulatory axis","volume":"116","author":"Wen RJ","year":"2023","journal-title":"Phytomed Int J Phytother 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