It is widely accepted that keto acids supplementation can protect skeletal muscle from atrophy. Pyroptosis has been considered to be one of the new mechanisms of muscle atrophy. This study aimed to explore the effects and mechanisms of keto acids supplementation on chronic kidney disease (CKD)-induced skeletal muscle atrophy. In vitro, C2C12 myoblast cells were treated with indoxyl sulfate (IS, 1 mM) and leucine (Leu, 0 ng/mL, 50 ng/mL or 100 ng/mL). In animal experiment, animals were divided into four groups: normal control (NC) group (wildtype mice), CKD group (wildtype mice with CKD modeling), keto acids (KAs) group (CKD wildtype mice treated with KA), and FNDC5-/- group (Fndc5 (irisin precursor) gene knockout mice with CKD modeling and KA treatment). Results showed that leucine improved IS-induced myotube atrophy, decreased percentage of Propidium Iodide (PI)-positive cells, upregulated FNDC5 expression levels, and downregulated the pyroptosis-related protein levels, such as NLRP3, cleaved CASP1, and GSDMD-N. KA supplementation improved renal function and skeletal muscle atrophy. Furthermore, KA supplementation suppressed the expression of pyroptosis-related proteins and increased the expression of FNDC5. However, Fndc5 gene knockout partially reversed the protective effects of keto acids in CKD. In conclusion, our results showed for the first time that KA supplementation improves CKD-induced skeletal muscle atrophy by inhibiting pyroptosis and increasing expression of irisin/FNDC5. Our findings provide a novel insight into the treatment of the CKD-induced skeletal muscle atrophy.© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.