GGT1 protects against calcium oxalate crystal-induced renal tubular epithelial cell injury by targeting GCLC.

Nephrolithiasis is a prevalent urological disorder in which calcium oxalate (CaOx) stones are most common, and accumulating evidence suggests that oxidative stress and ferroptosis contribute to CaOx-induced tubular epithelial injury. In this study, glyoxylic acid–induced mouse nephrocalcinosis and CaOx-stimulated HK-2 cells were used to explore the role of gamma-glutamyltransferase 1 (GGT1), a key enzyme in glutathione metabolism. RNA sequencing and qRT-PCR analyses identified GGT1 as a significantly downregulated gene in both models, and bioinformatic prediction followed by molecular validation demonstrated its interaction with the glutamate-cysteine ligase catalytic subunit (GCLC). GGT1 overexpression enhanced SLC7A11 and GPX4 expression while suppressing ACSL4, thereby reducing lipid peroxidation, mitigating oxidative stress, and alleviating tubular injury, whereas co-silencing GCLC attenuated these protective effects. These findings reveal that GGT1 safeguards against CaOx-induced nephrotoxicity by targeting GCLC to regulate ferroptosis and highlight GGT1 as a potential therapeutic target in nephrolithiasis.