Introduction: Protein-energy waste (PEW) is a common complication in patients with chronic kidney disease (CKD), among which skeletal muscle atrophy is one of the most important clinical features of PEW. Pyroptosis is a type of proinflammatory programmed cell death associated with skeletal muscle disease. Irisin, as a novel myokine, has attracted extensive attention for its protective role in the complications associated with CKD, but its role in muscle atrophy in CKD is unclear.Methods: Palmitic acid (PA) induced muscular atrophy was evaluated by a reduction in C2C12 myotube diameter. Muscle atrophy model was established in male C57BL/6J mice treated with 0.2% adenine for 4 weeks and then fed a 45% high-fat diet.BUN and Cr levels,body and muscle weight, and muscle histology were assessed. The expression of carnitine palmitoyltransferase 1A (CPT1A) and pyroptosis-related protein was analysed by western blots or immunohistochemistry. The release of IL-1 beta was detected by ELISA.Results: In this study, we showed that PA induced muscular atrophy and manifested as a reduction in C2C12 myotube diameter. During this process PA can also induce pyroptosis, as shown by the upregulation of NLRP3, cleaved Caspase1 and GSDMD-N expression and the increased IL-1 beta release and PI-positive cell rate. Inhibition of Caspase1 or NLRP3 attenuated PA-induced pyroptosis and myotube atrophy in C2C12 cells. Importantly, Irisin treatment significantly ameliorated PA-induced skeletal muscle pyroptosis and atrophy. In terms of mechanism, PA upregulated CPT1A, a key enzyme of fatty acid oxidation(FAO), and Irisin attenuated this effect, which was consistent with Etomoxir (CPT1A inhibitor) treatment. Moreover, Irisin improved skeletal muscle atrophy and pyroptosis in adenine-induced mice by regulating FAO. Conclusion: Our study firstly verifies that pyroptosis is a novel mechanism of skeletal muscle atrophy in CKD. Irisin ameliorated skeletal muscle atrophy by inhibiting FAO and pyroptosis in CKD, and Irisin may be developed as a potential therapeutic agent for the treatment of muscle wasting in CKD patients.