FBXL22 is a cardiac-enriched F-box protein that functions as a substrate recognition component of SCF-type E3 ubiquitin ligase complexes 1. It localizes to the sarcomeric z-disc and promotes proteasome-dependent ubiquitination and degradation of key sarcomeric proteins, including α-actinin-2 and filamin-C 1. FBXL22 plays dual roles in muscle: it is essential for maintaining normal cardiac contractile function through regulated turnover of sarcomeric proteins 1, yet also functions as a muscle atrophy-promoting ligase during neurogenic muscle atrophy 2. In vivo overexpression induces myopathy and atrophy, while knockdown protects against denervation-induced muscle loss 2. During cardiac regeneration, FBXL22 expression is regulated by AP-1 transcription factors and promotes sarcomere disassembly to facilitate cardiomyocyte dedifferentiation and proliferation 3. Beyond cardiac and skeletal muscle, FBXL22 has emerged as a disease-associated gene: hypomethylation of FBXL22 is associated with increased relapse risk in pediatric B-ALL 4, and rare variants are associated with triple-negative breast cancer risk in African American women 5. FBXL22 was also identified as a shared biomarker in osteoporosis and sarcopenia 6.