This study aimed to investigate the therapeutic potential of luteolin (LUT) in mitigating hyperoxaluria-induced renal inflammatory damage and calcium oxalate (CaOx) crystallization, while elucidating its underlying mechanisms against hyperoxaluria-driven nephrolithiasis.

Potential targets of LUT and nephrolithiasis were retrieved from multiple biomedical databases for network pharmacology analysis, followed by identification of critical pathways. Molecular docking and dynamics simulations validated ligand-target interactions. Experimental validation was performed using glyoxylate-induced murine nephrolithiasis models and hyperoxaluric HK-2 cells.

Network pharmacology analysis identified 223 targets associated with kidney stones and LUT (Luteolin). KEGG database enrichment analysis highlighted the involvement of several key pathways, including the PI3K-Akt signaling pathway, MAPK signaling pathway, HIF-1 signaling pathway, apoptosis, and IL-17 signaling pathway, in the treatment mechanisms of kidney stones and the therapeutic effects of LUT. Molecular docking and dynamics simulations demonstrated that LUT effectively binds to p85α, a critical regulatory subunit of the PI3K-Akt pathway. Histological studies revealed that LUT significantly reduced renal calcium crystal deposition in a mouse model of glyoxylic acid-induced kidney stones. Additionally, LUT alleviated renal apoptosis, oxidative damage, and levels of inflammatory factors. Molecular investigations showed that LUT inhibited the activation of the PI3K-Akt signaling pathway and suppressed the production of inflammatory factors in HK2 cells exposed to high oxalate levels.

LUT demonstrates multi-target inhibitory effects on nephrolithiasis progression through PI3K/Akt pathway modulation, offering novel therapeutic foundations for phytochemical-based management of renal calculi.