{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T06:33:46Z","timestamp":1792996426320,"version":"4.5.0"},"reference-count":57,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"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":["82202609"],"award-info":[{"award-number":["82202609"]}],"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":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Osteoarthritis (OA) is characterised by progressive articular cartilage degeneration, yet effective disease\u2010modifying targets remain limited. The post\u2010translational mechanisms sustaining Hedgehog\/\n                      <jats:italic>GLI1<\/jats:italic>\n                      signalling during OA progression remain incompletely understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Bioinformatic analyses of GEO datasets were performed to evaluate\n                      <jats:italic>GLI1<\/jats:italic>\n                      expression across OA\u2010related tissue compartments. Independent cartilage datasets, paired human cartilage specimens, and primary human chondrocytes exposed to graded IL\u20101\u03b2 stimulation provided tissue\u2010 and cell\u2010relevant evidence. An unbiased deubiquitinase library screen combined with\n                      <jats:italic>GLI1<\/jats:italic>\n                      \u2010responsive luciferase assays was used to identify\n                      <jats:italic>GLI1<\/jats:italic>\n                      \u2010regulating deubiquitinases. The molecular function of USP25, its reciprocal regulation with\n                      <jats:italic>GLI1<\/jats:italic>\n                      , and the preclinical chondroprotective activity and target dependence of AZ1 were investigated in vitro and in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>GLI1<\/jats:italic>\n                      dysregulation in OA cartilage and primary human chondrocytes supported subsequent screening, which prioritised USP25 for mechanistic study. In paired cartilage from 24 OA patients, USP25 protein abundance was higher in grossly degenerated than in relatively preserved regions and showed a modest positive correlation with\n                      <jats:italic>GLI1<\/jats:italic>\n                      . USP25 directly interacted with\n                      <jats:italic>GLI1<\/jats:italic>\n                      , removed K48\u2010linked polyubiquitin chains, and limited its proteasomal degradation. Reciprocal gain\u2010 and loss\u2010of\u2010function and rescue experiments indicated that\n                      <jats:italic>GLI1<\/jats:italic>\n                      substantially, but not exclusively, mediated USP25\u2010associated inflammatory and cartilage\u2010catabolic phenotypes.\n                      <jats:italic>GLI1<\/jats:italic>\n                      , in turn, bound the\n                      <jats:italic>USP25<\/jats:italic>\n                      promoter and enhanced\n                      <jats:italic>USP25<\/jats:italic>\n                      transcription, establishing a reciprocal regulatory circuit. AZ1 showed preclinical chondroprotective activity in primary human chondrocytes and DMM mice. Residual AZ1 activity after USP25 silencing indicated partial USP25 dependence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings define a\n                      <jats:italic>GLI1<\/jats:italic>\n                      \u2010centred mechanistic branch of USP25 biology in OA\u2010relevant models and provide tissue\u2010level support for coordinated USP25\u2010\n                      <jats:italic>GLI1<\/jats:italic>\n                      expression in human OA cartilage. The reciprocal USP25\u2010\n                      <jats:italic>GLI1<\/jats:italic>\n                      circuit contributes to cartilage\u2010catabolic phenotypes, while AZ1 provides preclinical proof\u2010of\u2010concept as a pharmacological probe. Further studies are warranted to define target selectivity, long\u2010term safety, and clinical relevance.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70851","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T09:45:18Z","timestamp":1790588718000},"source":"Crossref","is-referenced-by-count":0,"title":["USP25 stabilises\n                    <i>GLI1<\/i>\n                    through K48\u2010linked deubiquitination within a reciprocal regulatory circuit in osteoarthritis models"],"prefix":"10.1002","volume":"16","author":[{"given":"Qian","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Rehabilitation Medicine The Seventh Affiliated Hospital Sun Yat\u2010sen University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinyan","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine The Seventh Affiliated Hospital Sun Yat\u2010sen University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijie","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine The Seventh Affiliated Hospital Sun Yat\u2010sen University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1227-6939","authenticated-orcid":false,"given":"Jun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology The Seventh Affiliated Hospital Sun Yat\u2010sen University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7958-4082","authenticated-orcid":false,"given":"Dongfeng","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine The Seventh Affiliated Hospital Sun Yat\u2010sen University  Shenzhen 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