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However, how this fusion protein is regulated in cells remains unknown. Here, using multiple screenings, it is reported that Rab22a\u2010NeoF1 fusion protein is degraded by an E3 ligase STUB1 via the autophagy receptor NDP52\u2010mediated lysosome pathway, which is facilitated by PINK1 kinase. Mechanistically, STUB1 catalyzes the K63\u2010linked ubiquitin chains on lysine112 of Rab22a\u2010NeoF1, which is responsible for the binding of Rab22a\u2010NeoF1 to NDP52, resulting in lysosomal degradation of Rab22a\u2010NeoF1. PINK1 is able to phosphorylate Rab22a\u2010NeoF1 at serine120, which promotes ubiquitination and degradation of Rab22a\u2010NeoF1. Consistently, by upregulating PINK1, Sorafenib and Regorafenib can inhibit osteosarcoma lung metastasis induced by Rab22a\u2010NeoF1. These findings reveal that the lysosomal degradation of Rab22a\u2010NeoF1 fusion protein is targetable for osteosarcoma lung metastasis, proposing that Sorafenib and Regorafenib may benefit cancer patients who are positive for the\n                    <jats:italic>RAB22A<\/jats:italic>\n                    \u2010NeoF1 fusion gene.\n                  <\/jats:p>","DOI":"10.1002\/advs.202205483","type":"journal-article","created":{"date-parts":[[2022,12,18]],"date-time":"2022-12-18T22:21:07Z","timestamp":1671402067000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Targeting the Lysosomal Degradation of Rab22a\u2010NeoF1 Fusion Protein for Osteosarcoma Lung Metastasis"],"prefix":"10.1002","volume":"10","author":[{"given":"Cuiling","family":"Zeng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oncology in South China Sun Yat\u2010sen University Cancer Center Collaborative Innovation Center for 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