Epigallocatechin Gallate Attenuates CaOx Crystal-Induced Renal Tubular Injury to Inhibit CaOx Nephrolithiasis via GRP94/PI3K/AKT Signaling

Although tea consumption has been suggested to affect kidney stone formation, epidemiological evidence remains inconsistent, and the underlying molecular mechanisms are unclear. To assess the association between tea intake and kidney stone risk, we initially conducted a prospective cohort analysis of 481,393 participants from the UK Biobank and a 2-sample Mendelian randomization (MR) analysis. Our findings revealed that heavy tea drinkers (>5 cups/day) had a significantly reduced risk of kidney stones (hazard ratio: 0.79, 95% confidence interval [CI]: 0.72 to 0.86, P < 0.001), and MR analyses confirmed a causal association (inverse variance weighted OR: 0.45, 95% CI: 0.32 to 0.62, P < 0.001). We next explored the effect of epigallocatechin gallate (EGCG), the main bioactive component in tea, on calcium oxalate (CaOx) stone formation. EGCG was found to inhibit the glucose-regulated protein 94/phosphatidylinositol 3-kinase/protein kinase B (GRP94/PI3K/AKT) pathway in human proximal renal tubular epithelial cells, thereby attenuating CaOx crystal-induced oxidative stress and inflammation, and inhibiting crystal-cell adhesion. This finding aligned with the observation that the activated GRP94/PI3K/AKT pathway was positively associated with inflammation-related molecules in renal papillary tissues of CaOx stone formers. Moreover, to enhance renal targeting and therapeutic potential, we synthesized cell membrane-coated EGCG-loaded poly(lactic-co-glycolic acid) (TP-EGCG) nanoparticles, which enhanced renal EGCG delivery and substantially reduced CaOx crystal deposition in a mouse model of CaOx nephrolithiasis. In conclusion, tea consumption protects against kidney stone formation, an effect exerted by EGCG through the GRP94/PI3K/AKT axis, and our novel TP-EGCG nanoparticles show strong potential for targeted prevention and treatment.