Luteolin prevents hyperoxaluria-induced renal injury by inhibiting crystal deposition and renal inflammation.

Abstract

OBJECTIVE: To evaluate the protective effects of Luteolin (LUT) against hyperoxaluria-induced renal injury and calcium oxalate (CaOx) crystal deposition, and to explore the underlying molecular mechanisms. METHOD: The targets related to LUT and kidney stones were screened in a variety of databases, and the potential targets and pathways were identified by network pharmacology. Subsequently, the interaction between LUT and the core targets was verified by molecular docking and molecular dynamics simulation. Finally, a glyoxylate-induced kidney stone mouse model and high oxalate-induced HK2 cells were used to verify the effect and potential mechanism of LUT on kidney stone formation. RESULTS: Network pharmacology identified 223 intersecting targets between kidney stones and LUT, with KEGG enrichment highlighting the PI3K/Akt signaling pathway. Molecular docking revealed a strong binding affinity between LUT and p85α (-6.947 kcal/mol), and molecular dynamics simulations confirmed complex stability after 25 ns. In vivo, LUT significantly reduced renal calcium oxalate (CaOx) crystal deposition and alleviated tissue injury in the mouse model. In vitro, LUT effectively inhibited oxalate-induced PI3K/Akt activation and inflammatory cytokine production in HK-2 cells. Furthermore, CETSA analysis suggested a potential target engagement between LUT and p85α. CONCLUSION: This study suggests a protective effect of LUT against kidney stone formation at multiple levels. Our results indicate that LUT attenuates renal calcium crystal deposition, potentially through the inhibition of the PI3K/Akt signaling pathway. These findings provide new insights into the use of natural products for the prevention of nephrolithiasis.