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Pyropheophorbide\u2010a methyl ester\u2010Photodynamic therapy (MPPa\u2010PDT) is a new approach for the clinical treatment of osteosarcoma that develops after surgery and radiotherapy; however, the presence of MPPa\u2010PDT resistance in osteosarcoma greatly limits its efficacy. In this study, we found that Rho\u2010associated coiled\u2010coil containing protein kinase 2 (ROCK2) expression increased in osteosarcoma cells after MPPa\u2010PDT treatment. ROCK2 inhibition results in osteosarcoma sensitivity to MPPa\u2010PDT and is accompanied by a decrease in cellular autophagy levels. Rescue experiments further showed that ROCK2 mediates MPPa\u2010PDT resistance in osteosarcoma by regulating autophagy. Mechanistic studies have shown that ROCK2 mediates autophagy in osteosarcoma cells by regulating the Hippo signalling pathway. ROCK2 overexpression resulted in increased levels of the ROCK2\u2010Salvador homology 1 (SAV1) complex and decreased levels of the mammalian STE20\u2010like protein kinase 1 (MST1)\u2010SAV1 complex, thereby inhibiting activation of the Hippo pathway, which in turn led to osteosarcoma MPPa\u2010PDT resistance by regulating cellular autophagy. ROCK2 competes with MST1 for binding to the aa 28\u2013198 region of SAV1. We also confirmed from a clinical perspective that ROCK2 is an independent prognostic factor in patients with osteosarcoma, is associated with worse patient prognosis, and correlates with the Hippo pathway. Targeted inhibition of ROCK2 by screening for J059\u20100149 increases the sensitivity of osteosarcoma to MPPa\u2010PDT. In conclusion, our study establishes a novel mechanism to reverse MPPa\u2010PDT resistance in osteosarcoma by targeting ROCK2\u2010mediated autophagy, providing new targets and research ideas for the clinical treatment of osteosarcoma MPPa\u2010PDT resistance.<\/jats:p>","DOI":"10.1111\/cpr.70097","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T02:14:02Z","timestamp":1752718442000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Reversal of\n                    <scp>MPPa<\/scp>\n                    \u2010\n                    <scp>PDT<\/scp>\n                    Resistance in Osteosarcoma by Targeting\n                    <scp>ROCK2<\/scp>\n                    \u2010Mediated Autophagy"],"prefix":"10.1111","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7701-8888","authenticated-orcid":false,"given":"Xuan","family":"Yi","sequence":"first","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Nanchang University  Nanchang China"},{"name":"Institute of Orthopedics of Jiangxi Province  Nanchang China"},{"name":"Jiangxi Provincial Key Laboratory of Spine and Spinal Cord Disease  Nanchang China"},{"name":"Institute of Minimally Invasive Orthopedics Nanchang University  Nanchang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0003-7092","authenticated-orcid":false,"given":"Xueqiang","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Nanchang University  Nanchang China"},{"name":"Department of Rehabilitation The Second Affiliated Hospital of Nanchang University  Nanchang 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