Gut microbiota-derived tryptophan metabolite attenuates calcium oxalate nephropathy by suppressing renal tubular cell apoptosis through the AhR-SOCS3-STAT1 axis.

Calcium oxalate (CaOx) nephropathy is a highly prevalent urological disease worldwide. Gut microbiota dysbiosis and host metabolic dysregulation are recognized as pivotal drivers in disease pathogenesis, yet the underlying mechanisms remain incompletely understood. In this study, by integrating metagenomics and metabolomics, we identified dysregulation of tryptophan metabolites in patients with CaOx nephrolithiasis, with microbiota-derived indole-3-propionic acid (IPA) as the most discriminatory differential metabolite. Oral IPA supplementation markedly reduced renal CaOx crystal deposition and tubular injury in a CaOx nephropathy murine model. Mechanistically, IPA activated the aryl hydrocarbon receptor (AhR), which translocated to the nucleus and transcriptionally upregulated suppressor of cytokine signaling 3 (SOCS3)-a negative regulator of signal transducer and activator of transcription 1 (STAT1)-thereby suppressing STAT1 phosphorylation, alleviating oxalate-induced tubular cell injury and apoptosis, and inhibiting CaOx crystal deposition. Our findings identify tryptophan metabolite alteration as a critical metabolic signature of CaOx nephropathy and demonstrate that microbiota-derived IPA attenuates oxalate-induced renal tubular cell injury and apoptosis via the AhR-SOCS3-STAT1 axis. © 2026 The Pathological Society of Great Britain and Ireland.