This study aims to investigate the role of hypercalciuria and pyroptosis in the formation of calcium oxalate kidney stones. Bioinformatics analysis was performed to compare the correlation of pyroptosis scores and cell adhesion scores between Randall's plaques and normal tissues from kidney stone patients. For the in vitro experiments, we investigated the effects of high concentrations of Ca2+ on the pyroptosis and adhesion levels of renal tubular epithelial cells and examined the adhesion levels and crystal aggregation of the cells in high Ca2+ concentrations environment by knockdown and overexpression of the key pyroptosis gene, GSDMD, and we verified the effects of Ca2+ concentration on pyroptosis and adhesion levels, kidney injury, and crystal deposition by in vivo experiments. Bioinformatic results showed that the scores of pyroptosis and cell adhesion in Randall's plaques of patients with kidney stones were significantly higher than those in normal tissues, and pyroptosis was highly positively correlated with cell adhesion. In vitro and in vivo experiments showed that high concentrations of Ca2+ activated the NLRP3/Caspase-1/GSDMD pathway of pyroptosis through ROS and up-regulated the expression of adhesion-related proteins, and GSDMD could regulate the adhesion level of renal tubular epithelial cells by mediating the level of pyroptosis, thereby affecting the adhesion and deposition of calcium oxalate crystals. Our findings reveal that the Ca2+-induced classical pyroptosis pathway may be a potential mechanism to promote calcium oxalate kidney stone formation, which provides new insights into the etiology of kidney stones.© 2025. The Author(s).