From microbial tryptophan metabolism to crystal injury: an IPA-AhR checkpoint in calcium oxalate nephropathy.

Calcium oxalate nephrolithiasis is commonly viewed as a consequence of urinary supersaturation, although crystal retention and renal injury are also influenced by gut microbiota dysbiosis and local tissue environment. In a recent study by Li et al, published in The Journal of Pathology, the authors integrated human metagenomic and metabolomic analyses with mouse and tubular cell models to identify indole-3-propionic acid (IPA) as a key gut-derived metabolite associated with kidney stone disease. Patients with calcium oxalate stones showed altered gut microbial composition and reduced serum IPA levels, which were inversely related to stone burden. In experimental models, IPA supplementation reduced renal crystal deposition, preserved kidney function, and limited tubular injury and apoptosis. Mechanistic studies showed that IPA activated aryl hydrocarbon receptor (AhR) in tubular epithelial cells, increased suppressor of cytokine signaling 3 (SOCS3) expression, and suppressed signal transducer and activator of transcription 1 (STAT1) phosphorylation and nuclear accumulation. These findings were supported by complementary activation, inhibition, knockdown, and overexpression experiments. Collectively, the data suggest that IPA protects renal epithelial cells through the AhR-SOCS3-STAT1 signaling pathway and may offer a potential therapeutic approach for calcium oxalate nephropathy. © 2026 The Pathological Society of Great Britain and Ireland.