Lysimachia christinae Hance Extract Mitigates Kidney Stone Formation: Association with NOX2/ROS Axis Modulation and Ferroptosis.

Kidney stone disease is a common urinary system disorder with a continuously rising global incidence, posing a major public health challenge. As a classic traditional Chinese medicine for the treatment of kidney stones, Lysimachia christinae Hance (LCH) has not yet been fully elucidated in terms of its pharmacological mechanism. In this study, a rat model of calcium oxalate kidney stones and a calcium oxalate monohydrate (COM)-induced injury model of human renal tubular epithelial (HK-2) cells were established. Combined with transcriptomic analysis and experimental verification, the therapeutic effect and underlying molecular mechanism of LCH against kidney stones were systematically explored. Results demonstrated that LCH extract significantly reduced serum levels of blood urea nitrogen (BUN) and creatinine (Cr), as well as renal tissue levels of kidney injury molecule-1 (KIM-1) and cystatin-C (Cys-C) in rats with calcium oxalate crystal-induced renal injury, and diminished calcium oxalate crystal deposition and adhesion in rat renal tissues as well as HK-2 cells, thus exerting a robust renoprotective effect. Mechanistically, transcriptome sequencing indicated that the anti-nephrolithiasis effect of LCH was closely related to the inhibition of oxidative stress and ferroptosis. LCH extract reversed CaOx crystal-induced upregulation of NADPH oxidase 2 (NOX2) and downregulation of superoxide dismutase 2 (SOD2), reduced intracellular oxygen species (ROS) levels, downregulated the expression of transferrin receptor 1 (TFR1) and acyl-CoA synthetase long-chain family member 4 (ACSL4) while upregulating that of ferritin heavy chain 1 (FTH1), solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), and diminished intracellular iron accumulation, thereby effectively ameliorating crystal-mediated renal injury. The present study demonstrates that the therapeutic effect of LCH on kidney stones is closely related to the regulation of the NOX2/ROS signaling axis and ferroptosis, providing novel theoretical evidence for its clinical application.