Environmental Exposure to Melamine Derivatives and Early Kidney Injury: Role of Ferroptosis and Oxidative Stress

Melamine (MEL) and its derivatives are known for acute nephrotoxicity, but the risks from chronic exposure and underlying mechanisms of toxicity are unclear. We integrated environmental monitoring (356 pairs of house dust and urine samples collected across mainland China) with cell-based bioassays to investigate MEL exposure sources and toxic effects. MEL-related chemicals were frequently detected in dust (median: 10.3 μg/g) and urine (22.3 ng/mL) samples, indicating their widespread presence in indoor environments and chronic exposure among the Chinese population. Significant positive correlations were observed between MEL-related chemicals and neutrophil gelatinase-associated lipocalin (NGAL), a urinary biomarker of nephrotoxicity. RNA-sequencing of MEL-exposed human kidney-2 (HK-2) cells revealed significant enrichment of the ferroptosis signaling pathway. Further bioassays demonstrated that MEL exposure induces iron-driven mitochondrial lipid peroxidation in HK-2 cells. The system X_c^-/GPX4, ACSL4, and TFR1/DMT1 pathways identified as potential targets in ferroptosis-mediated early renal injury in both acute toxicity experiments and chronic exposure to environmentally relevant concentrations. This finding was further supported by urinary malondialdehyde and Fe²⁺ levels that mediated 13-31% of the effect of MEL-related chemicals on NGAL in humans. Our study provides valuable insights into the role of ferroptosis in chronic kidney injury associated with environmental exposure to MEL and its derivatives.