Nuclear Translocation of PFKFB3 Promotes Disuse-Induced Muscle Atrophy via Scaffolding Nedd4-Mediated JunB Ubiquitination.

Disuse-induced muscle atrophy is characterized by coordinated metabolic remodeling and enhanced protein degradation, yet the molecular link between these processes remains unclear. Here, we identify 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 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-atrophy factor, contributes to atrophic progression. In turn, JunB transcriptionally represses PFKFB3, forming a regulatory feedback loop. Pharmacological and genetic inhibition of the PFKFB3-Nedd4-JunB 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-induced muscle wasting.