Objective: To explore the role and regulation mechanism of leptin in MCM senescence of mouse cardiomyocytes. Methods：The mRNA expression levels of senescence related factors p16 and p21 after leptin stimulation of MCM were examined by qPCR; the protein expressions of p16, p21, PI3K, AKT, p-PI3K and p-AKT were detected by Western Blot; the senescence of MCM was detected by β-galactosidase staining. PI3K inhibitor (LY294002) was pretreated for 2h and then stimulated with leptin , The mRNA level and protein expression of p16 and p21 was detected by qPCR and Western Blot；the mRNA level of senescence-associated secretory phenotype (SASP) was examined by qPCR; MCM senescence was detected by β-galactosidase staining. Results: Leptin up-regulated the mRNA and protein expressions of p16 and p21.After leptin treatment, the phosphorylation level of PI3K/AKT signal were increased; and β -galactosidase staining illustrated the senescence of MCM. After pretreatment with PI3K inhibitor for 2h, the expression of senescence-related proteins p16 and p21 were down-regulated; the senescence of MCM was alleviated; and the expressions of SASP (IL-1β, TNF-α、IL-6 and MCP-1) mRNA were down-regulated. Conclusion: Leptin regulates the progression of MCM senescence by activating PI3K/AKT signal and promoting SASP (IL-1β, TNF-α、IL-6 and MCP-1) secretion.