Phenylalanine primes renal tubular redox vulnerability and calcium oxalate crystal retention through a PPARδ-CPT1A fatty-acid oxidation axis.

Calcium oxalate (CaOx) nephrolithiasis is usually framed as a physicochemical disorder of urinary supersaturation, yet stable crystal retention also requires a permissive tubular epithelial state. Here, we tested whether circulating phenylalanine (Phe) functions as a systemic priming factor that sensitizes renal tubular epithelium to CaOx crystal retention under lithogenic stress. Targeted amino-acid metabolomics in patients with CaOx stones, two-sample Mendelian randomization, glyoxylate-induced mouse nephrolithiasis, HK-2 cell injury assays, renal transcriptomics, pathway-rescue experiments and a Corydalis yanhusuo polysaccharide (CYPN-1) intervention were integrated in a staged translational design. Plasma Phe was elevated in CaOx stone formers, and genetically predicted Phe was positively associated with kidney stone risk without evidence of reverse causality. Phe loading did not independently generate stones but markedly amplified glyoxylate-induced renal crystal deposition and oxalate-triggered crystal adhesion to tubular epithelial cells. Mechanistically, Phe suppressed a PPARδ-CPT1A fatty acid oxidation program, increased reactive oxygen species and lipid peroxidation, and induced a redox-lipotoxic tubular phenotype. Activation of PPARδ or CPT1A rescued fatty acid oxidation signaling, lowered oxidative injury and reduced crystal burden in vitro and in vivo. CYPN-1 lowered circulating Phe, reshaped Phe-related gut microbial functions, restored tubular PPARδ-CPT1A signaling and attenuated crystal deposition. These data identify Phe as a modifiable metabolic sensitizer of tubular redox vulnerability under lithogenic stress and support CaOx nephrolithiasis as a disease in which luminal crystallization and circulation-facing metabolic injury converge at the renal tubule.