Nephrolepis cordifolia Extracts Attenuate Calcium Oxalate Nephrolithiasis Through Redox Modulation and Suppression of Crystal Retention

Calcium oxalate (CaOx) nephrolithiasis is closely associated with crystal-induced oxidative injury, impaired antioxidant defenses, and enhanced crystal retention in renal tissues. Nephrolepis cordifolia is a medicinal fern traditionally used for urinary tract-related disorders and edema, but its antioxidant-related protective activity against CaOx nephrolithiasis has not been systematically investigated. In this study, ethanol and water extracts of Nephrolepis cordifolia tubers were evaluated using CaOx crystallization assays, HEK293T cell-based oxidative stress assays, and a glyoxylate-induced mouse model. The extracts inhibited CaOx crystal growth and aggregation and shifted SEM-observed crystal morphology from calcium oxalate monohydrate-like aggregates toward less adhesive calcium oxalate dihydrate-like forms. FTIR spectra further indicated extract-associated changes in the structural and hydration characteristics of the resulting CaOx crystals. In cells, the extracts showed good cytocompatibility and reduced intracellular reactive oxygen species. In vivo, both extracts reduced renal crystal deposition and histopathological injury, restored antioxidant defenses, decreased malondialdehyde accumulation, downregulated CD44 and osteopontin expression, and improved serum and urinary biochemical abnormalities. The water extract generally produced stronger protection than the ethanol extract. LC–MS profiling of both ethanol and water extracts annotated diverse constituents, including flavonoid-related compounds, glycosides, phenolic constituents, terpenoid-related molecules, and lipid-associated components. These findings indicate that Nephrolepis cordifolia extracts mitigate CaOx nephrolithiasis partly by restoring redox homeostasis and limiting oxidative injury-associated crystal retention.