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Although proteostasis supports tumor growth, the mechanism by which ubiquitin ligases reprogram chaperone networks to drive metastasis is poorly understood. In this study, it is revealed that DDB1\u2010CUL4\u2010associated factor (DCAF12), a substrate receptor for CUL4\u2010RING ubiquitin ligases, regulates metastatic progression through ubiquitin\u2010mediated proteostatic reprogramming. DCAF12 depletion suppresses tumor cell migration and stemness in vitro and reduces pulmonary\/hepatic metastasis in vivo. Mechanistically, DCAF12 catalyzes the non\u2010degradative ubiquitination of TRiC\/CCT subunits, enhancing chaperonin assembly and folding of cytoskeletal effectors (\u03b2\u2010actin\/tubulin) and oncogenic clients (STAT3\/Raptor\/mLST8), thereby activating the YAP, STAT3, and mTOR pathways. Both genetic knockdown and pharmacological blockade (via HSF1A) of this axis potently inhibit metastasis. Clinically, DCAF12 overexpression is correlated with YAP\/STAT3 activation, advanced metastasis, and poor survival. Three key insights are revealed: 1) ubiquitination\u2010mediated TRiC\/CCT regulation as a metastatic switch, 2) DCAF12 as an oncogenic proteostasis hub, and 3) therapeutic potential validated through multimodal targeting. These findings establish the DCAF12\u2010TRiC\/CCT axis as a mechanistically novel target that simultaneously disrupts cytoskeletal dynamics and oncogenic signaling,\u00a0making it a promising therapeutic strategy for metastatic lung cancer.<\/jats:p>","DOI":"10.1002\/advs.202509695","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T03:19:58Z","timestamp":1759720798000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DCAF12 Ubiquitin Ligase Promotes Lung Cancer Metastasis by Modulating the TRiC\/CCT Chaperonin Complex"],"prefix":"10.1002","volume":"13","author":[{"given":"Zhenyi","family":"Wang","sequence":"first","affiliation":[{"name":"Medical Research Center The First Affiliated Hospital of Wenzhou Medical University  Wenzhou Zhejiang 325015 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