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

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.