Microcystin‐LR Triggers Renal Tubular Ferroptosis Through Epigenetic Repression of GPX4: Implications for Environmental Nephrotoxicity

Abstract Environmental toxins represent a growing public health concern. Microcystin‐LR (MC‐LR), a potent cyanobacterial toxin found in freshwater ecosystems, has been linked to multisystem toxicity. However, its impact on renal pathology ‐ particularly through regulated cell death ‐ remains poorly characterized. This study investigates the molecular basis of MC‐LR‐induced nephrotoxicity in murine models, focusing on ferroptosis and epigenetic regulation. Using both acute and chronic MC‐LR exposure paradigms, marked kidney fibrosis and ferroptosis are observed, evidenced by lipid peroxidation, mitochondrial damage, and collagen deposition. Mechanistically, MC‐LR suppressed transcription of glutathione peroxidase 4 (GPX4) in tubular epithelial cells. This downregulation is associated with promoter hypermethylation, increased expression of DNA methyltransferases DNMT1 and DNMT3a, and enhanced recruitment of the transcriptional repressor E2F4 and co‐repressor NCoR. Notably, MC‐LR directly bound DNMT1 and DNMT3a, stabilizing their protein levels by blocking proteasomal degradation. Pharmacological inhibition of DNA methyltransferases (SGI‐1027) or ferroptosis (ferrostatin‐1) significantly ameliorated renal injury. These findings uncover a previously unrecognized epigenetic mechanism by which MC‐LR drives ferroptosis and kidney damage. Targeting the DNMT‐GPX4 axis may offer therapeutic opportunities for mitigating toxin‐induced organ injury and protecting public health against environmental biohazards.