Cadmium exposure upregulates TXNIP and aggravates calcium oxalate kidney stone formation by promoting cell-crystal adhesion, apoptosis and macrophage M1 polarization.

We systematically evaluated how cadmium (Cd) exposure synergizes with calcium oxalate (CaOx) to promote kidney stone formation and renal injury, focusing on the central role of thioredoxin-interacting protein (TXNIP). Clinical kidney stones, in vitro assays, and mouse models were analyzed. X-ray diffraction and inductively coupled plasma analysis confirmed cadmium accumulation in stones. In vitro, cadmium chloride altered CaOx crystal morphology, surface energy, and zeta potential, enhancing crystal adhesion, deposition, and aggregation on renal epithelial cells. Transcriptomic sequencing and bioinformatic enrichment identified pathways activated by combined Cd and CaOx exposure. In a murine kidney stone model, co-exposure increased renal crystal deposition, fibrosis, inflammation, and functional impairment. Tubular epithelial cells exhibited elevated CXCL5 secretion, promoting macrophage chemotaxis and polarization toward a pro-inflammatory M1 phenotype, thereby establishing a fibrogenic microenvironment. TXNIP was markedly upregulated; its knockdown reduced crystal adhesion, M1 polarization, activation of the ASK1-JNK-Caspase-3 apoptotic pathway, interstitial fibrosis, and tubular apoptosis, preserving renal function. These findings reveal that cadmium accelerates CaOx stone formation and kidney injury by driving a TXNIP-mediated oxidative stress-inflammation-apoptosis axis. Targeting TXNIP may offer a novel therapeutic strategy to disrupt this pathogenic feedback loop and prevent toxin-associated kidney stones and renal damage.