Regulating the balance between GSDMD-mediated pyroptosis and CHMP4B-dependent cell repair attenuates calcium oxalate kidney stone formation.

An imbalance exists between renal tubular epithelial cells (RTECs) injury and repair in kidney stone disease, yet the underlying mechanism remains largely unclear. Here, we found that gasdermin D (GSDMD)-mediated pyroptosis occurred in both patients and mice with calcium oxalate (CaOx) nephrolithiasis, and the expression levels of NOD-like receptor protein 3 (NLRP3) and GSDMD were associated with the severity of kidney stones. Deficiency of GSDMD alleviated renal tubule damage and inflammatory response, ultimately inhibiting renal injury and crystal deposition. Additionally, we found that charged multivesicular body protein 4B (CHMP4B)-dependent cell repair was activated during pyroptosis of RTECs; however, the enhancement was insufficient to offset the damage. Importantly, Ca2+ fluxes during pyroptosis induce activation of the CHMP4B-dependent cell repair machinery. Overexpression of CHMP4B attenuates cell death and reduces the severity of kidney stones. Notably, combining the overexpression of CHMP4B with a GSDMD inhibitor demonstrates heightened efficacy in ameliorating kidney damage and crystal deposition induced by glyoxylate (Gly). Taken together, these results highlight the imbalance between GSDMD-mediated pyroptosis and CHMP4B-dependent cell repair as a driver for CaOx kidney stone formation. Our findings provide new insights and potential therapeutic targets for CaOx kidney stones.