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

TL;DR

This study shows how the toxin MC-LR causes kidney damage in mice by triggering a type of cell death called ferroptosis through epigenetic changes.

Contribution

The study reveals a novel epigenetic mechanism by which MC-LR induces ferroptosis and kidney injury.

Findings

MC-LR causes kidney fibrosis and ferroptosis through lipid peroxidation and mitochondrial damage.

MC-LR represses GPX4 transcription via promoter hypermethylation and recruitment of E2F4 and NCoR.

Pharmacological inhibition of DNA methylation or ferroptosis reduces MC-LR-induced kidney damage.

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.

MC‐LR stabilizes DNMT1/3a by blocking their ubiquitin‐mediated degradation, leading to Gpx4 promoter hypermethylation and E2F4/NCoR‐associated transcriptional repression, which drives renal tubular ferroptosis in mice. Pharmacological inhibition of DNA methylation (SGI‐1027) or ferroptosis (Fer‐1) disrupts this DNMT‐GPX4 axis, thereby alleviating MC‐LR‐induced ferroptosis and nephrotoxicity.

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