#1008

Luteolin Attenuates Hyperoxaluria-Driven Renal Inflammatory Pathology and Suppresses Calcium Oxalate Crystallization via Dual Mechanistic Pathways

Z. Jin¹, S. Zhu¹, T. Wang¹, Y. Wu¹

¹Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Department of Urology, Wuhan, China

Introduction:

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.

Material and methods:

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.

Results:

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.