Jujuboside A induces bladder cancer cell apoptosis by inhibiting ATP1A2-mediated mitochondrial energy metabolism regulation

BACKGROUND: Conventional treatments for bladder cancer exhibit various limitations. Therefore, natural products, such as jujuboside A (JuA), have been explored for their multi-target effects and low toxicity. However, the specific effects of JuA in bladder cancer remain unclear. OBJECTIVE: To determine whether JuA affects mitochondrial energy metabolism and apoptosis in bladder cancer cells by regulating the ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2) expression. METHODS: Differentially expressed genes (DEGs) in bladder cancer were analyzed using the GSE133624 dataset. ATP1A2 overexpression and knockdown bladder cancer cell models were constructed. Cell phenotypes and markers related to apoptosis and mitochondrial energy metabolism were assessed. Moreover, targeting effects of JuA were investigated. RESULTS: Interleukin (IL)-6, ATP1A2, and hydroxysteroid 11-beta dehydrogenase 1 were identified as potential JuA targets, with ATP1A2 being the main target. ATP1A2 overexpression enhanced the viability and inhibited the apoptosis of bladder cancer cells and promoted mitochondrial energy metabolism in vitro, whereas ATP1A2 knockdown had the opposite effects. JuA decreased cell viability, inhibited ATP1A2 expression, and disrupted mitochondrial energy metabolism. These anticancer effects of JuA were reversed by ATP1A2 overexpression. CONCLUSION: This study elucidated the molecular mechanism by which JuA regulates mitochondrial energy metabolism and induces apoptosis in bladder cancer cells through targeted inhibition of ATP1A2. These findings reveal the crucial role of ATP1A2 in the energy metabolism and survival of bladder cancer cells, providing a new molecular perspective for a deeper understanding of the pathological mechanisms of bladder cancer.