Sodium hexametaphosphate mitigates calcium oxalate stone formation by modulating crystallization and maintaining PPARα signaling.

Kidney stones are common diseases in the urinary system, characterized by high morbidity and recurrence rates, but effective drug treatments are limited. We chose sodium hexametaphosphate (HMP) to investigate its role in inhibiting calcium oxalate (CaOx) crystallization in vitro and in vivo. We predicted potential targets of HMP using bioinformatics, simulated drug molecular docking, and explored the molecular mechanism of HMP inhibition of CaOx stone formation in a cellular model and hyperoxaluria-induced crystallization rat model. HMP specifically adsorbed on high-energy crystal surfaces, inhibiting the growth of CaOx monohydrate (COM), significantly reducing crystal size, and promoting the conversion to CaOx dihydrate (COD). At higher concentrations, CaOx crystals transformed from micrometer to nanometer scale, achieving complete conversion from COM to COD and almost complete inhibition of CaOx crystal formation. Additionally, HMP significantly reduced oxidative damage caused by high oxalate in NRK-52E cells, decreased reactive oxygen species production, inhibited mitochondrial membrane potential depolarization, and subsequently inhibited cell apoptosis. By integrating the transcriptomic data and the crystallization results, HMP primarily acts by modulating CaOx crystallization, upregulating PPARα to promote fatty-acid transport and β-oxidation, thereby enhancing the expression of downstream antioxidant factors NRF2 and SOD1 and, in turn, attenuating hyperoxaluria-induced renal oxidative injury. The novel drug HMP, combining CaOx crystallization modulation and oxidative stress inhibition, may be a treatment option for kidney stones.