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Here, we identify 6\u2010phosphofructo\u20102\u2010kinase\/fructose\u20102,6\u2010bisphosphatase 3 (PFKFB3) as a critical regulator of this condition. Using a unilateral hindlimb immobilization mouse model, metabolomics, and functional assays in vivo and in vitro, we demonstrate that PFKFB3 is markedly upregulated during muscle atrophy and promotes myofiber wasting. Mechanistically, PFKFB3 predominantly localizes to the nucleus and functions independently of its canonical glycolytic activity. It acts as a scaffold protein to facilitate the interaction between the E3 ubiquitin ligase Nedd4 and the transcription factor JunB, thereby enhancing JunB ubiquitination and proteasomal degradation. Loss of JunB, a known anti\u2010atrophy factor, contributes to atrophic progression. In turn, JunB transcriptionally represses PFKFB3, forming a regulatory feedback loop. Pharmacological and genetic inhibition of the PFKFB3\u2013Nedd4\u2013JunB axis significantly attenuates muscle atrophy in vivo. Collectively, these findings reveal a noncanonical nuclear function of PFKFB3 in coordinating protein stability during muscle atrophy and highlight this signaling axis as a potential therapeutic target for disuse\u2010induced muscle wasting.<\/jats:p>","DOI":"10.1002\/advs.77854","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:46:32Z","timestamp":1789620392000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nuclear Translocation of PFKFB3 Promotes Disuse\u2010Induced Muscle Atrophy via Scaffolding Nedd4\u2010Mediated JunB Ubiquitination"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0572-4652","authenticated-orcid":false,"given":"Mengjun","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Orthopedics The Eighth Affiliated Hospital of Sun Yat\u2010Sen University  Shenzhen China"},{"name":"Biological Laboratory of Hetao 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