Kidney stone disease (KSD) is one of the most common urological disorders, and oxalate-induced tubular epithelial cell injury plays a crucial role in stone-related renal damage. However, the mechanisms linking oxalate exposure to mitochondrial dysfunction remain unclear. Urolithin A (UA), a gut microbiota-derived metabolite of ellagitannins, is recognized for its antioxidant and mitophagy-promoting properties. This study investigated the renoprotective effects and mechanisms of UA in calcium oxalate (CaOx) crystal-induced renal injury. In mice, UA markedly reduced renal CaOx deposition, improved renal function, and alleviated kidney injury. Consistently, both in vivo and in vitro experiments demonstrated that UA restored oxalate-suppressed mitophagy while also alleviating oxidative stress, apoptosis, and mitochondrial dysfunction. Transcriptomic and molecular docking analyses identified phosphoenolpyruvate carboxykinase 1 (PCK1) as a downstream target of UA. UA restored PCK1 expression under oxalate stress both in vivo and in vitro, whereas pharmacological inhibition of PCK1 weakened the renal protective and mitophagy-promoting effects. Conversely, PCK1 overexpression enhanced mitophagy under high-oxalate conditions. These findings indicate that UA alleviates CaOx-induced renal injury by activating PCK1-dependent mitophagy and restoring mitochondrial homeostasis. Given its natural origin and favorable safety profile, UA represents a promising candidate for preventing or treating calcium oxalate-associated renal injury.
