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Deregulated PRKCN is implicated in solid tumors, while its role in MM remains elusive. Here, PRKCN is identified as a super\u2010enhancer\u2010driven gene associated with adverse prognosis in MM. PRKCN is transactivated by NF\u2010\u03baB signaling intrinsically existing or exogenously provoked. Constitutive or inducible knockdown of PRKCN significantly impairs cell growth and tumorigenicity, while overcoming drug resistance. PRKCN harnesses IRF4 to exert its effect, and in turn, IRF4 directly induces PRKCN transcription, establishing a feed\u2010forward IRF4\u2010PRKCN circuit. Furthermore, PRKCN fosters IRF4 expression by activating mTORC1\/C2 signaling pathways via physical interaction with mTOR. Surprisingly, PRKCN modulates mTOR\u2010IRF4 axis and cell growth independently of its acknowledged kinase activity yet requiring activation loop phosphorylation. Intriguingly, PRKCN silencing evokes interferon signaling and confers increased sensitivity to interferon. Finally, targeting PRKCN with an orally bioavailable inhibitor suppresses MM cell growth and overcomes drug resistance in vitro, and elicits robust efficacy in cell line\u2010derived xenografts and a patient\u2010derived xenograft, which is connected with the mitigated PRKCN expression and activation loop phosphorylation as well as blunted mTOR\u2010IRF4 axis. Collectively, our study delineates PRKCN function that links aberrant NF\u2010\u03baB signaling and mTOR\u2010IRF4 axis, supporting clinically targeting PRKCN in MM.<\/jats:p>","DOI":"10.1002\/advs.202518975","type":"journal-article","created":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T18:06:59Z","timestamp":1770574019000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting PRKCN, an Essential Driver Orchestrating mTOR\u2010IRF4 Axis Independently of Kinase Activity, in Multiple Myeloma"],"prefix":"10.1002","volume":"13","author":[{"given":"Koukou","family":"Tang","sequence":"first","affiliation":[{"name":"Institute of Blood and Marrow Transplantation National Clinical Research Center for Hematologic Diseases Jiangsu Institute of Hematology Collaborative Innovation Center of Hematology The First Affiliated Hospital of Soochow University Soochow University  Suzhou Jiangsu 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