From crystals to damage: The emerging role of ferroptosis in calcium oxalate nephropathy (Review)

Nephrolithiasis is a major public health concern associated with high morbidity and recurrence rates, placing an immense burden on healthcare systems worldwide. Given that ferroptosis, an iron‑dependent, lipid peroxidation‑driven form of regulated cell death, has emerged as a key pathological mechanism in oxalate‑induced renal injury, it has gained increasing attention in nephrolithiasis research. It has been clearly demonstrated that ferroptosis actively promotes calcium oxalate (CaOx) crystal nucleation and adhesion, while CaOx deposition in turn exacerbates ferroptosis, forming a bidirectional positive feedback loop that amplifies renal damage. However, the molecular mechanisms regulating ferroptosis in kidney stone disease, including the roles of gut microbiota metabolites, sex hormone signaling, and epigenetic pathways, have not yet been fully elucidated. The present review presents a comprehensive summary of the existing literature on the mechanisms of ferroptosis in nephrolithiasis, including the SOX4/EZH2/SLC7A11 axis, inflammatory pathways (NF‑κB and JAK‑STAT3), oxidative/endoplasmic reticulum stress pathways, as well as ferroptosis‑targeted therapies (ferrostatin analogs, natural products and repurposed drugs). The present review aimed to advance the current understanding of ferroptosis regulation and its potential therapeutic applications in human kidney stone disease.