The m7G methyltransferase METTL1 promotes acute kidney inflammation by disrupting mitochondrial function

Kidney Int. 2026 Mar;109(3):489-505. doi: 10.1016/j.kint.2025.11.010. Epub 2025 Dec 15.

Abstract

Introduction: RNA modifications regulate the progression of inflammatory diseases. However, the role of N7-methylguanosine (m7G) modification and its regulatory enzyme, methyltransferase-like 1 (METTL1), in inflammatory kidney diseases remains poorly understood. Here, we aimed to investigate the function and underlying mechanisms of METTL1-mediated m7G modification in acute kidney injury (AKI).

Methods: Kidney tubular epithelial cell (TEC)-specific METTL1 conditional knockout mice were used to evaluate the functional role of METTL1 in multiple AKI mouse models (cisplatin, ischemia/reperfusion and cecal ligation/puncture). Additionally, kidney tissue was obtained from patients with AKI and from the non-tumor kidney tissue of patients with nephrectomy for kidney cancer. RNA sequencing and m7G-methylated RNA immunoprecipitation sequencing were performed to identify downstream targets and elucidate underlying mechanisms.

Results: Both m7G modification and METTL1 expression were markedly upregulated in TECs from patients and mice with AKI. TEC-specific deletion of METTL1 significantly attenuated kidney injury and inflammation in the multiple AKI mouse models. Mechanistically, METTL1-mediated m7G modification enhanced the stability of the TEA domain transcription factor 2 (TEAD2) mRNA by the binding protein Quaking. Elevated TEAD2 impaired mitochondrial function by transcriptionally repressing medium-chain acyl-CoA dehydrogenase (ACADM), thereby amplifying proinflammatory responses. METTL1 knockdown mediated by tetrahedral framework DNA nanostructures, as well as pharmacological inhibition with AZD1080, a novel METTL1 inhibitor, effectively alleviated the severity of AKI in mice in prevention and therapeutic approaches.

Conclusions: Our findings suggest that targeting the METTL1/TEAD2/ACADM axis may represent a potential therapeutic strategy for inflammatory kidney diseases.

Keywords: AKI; METTL1; TEAD2; inflammation; m(7)G; mitochondria.

MeSH terms

  • Acute Kidney Injury* / genetics
  • Acute Kidney Injury* / pathology
  • Animals
  • Disease Models, Animal
  • Epithelial Cells
  • Humans
  • Kidney Tubules / cytology
  • Kidney Tubules / pathology
  • Male
  • Methyltransferases* / antagonists & inhibitors
  • Methyltransferases* / genetics
  • Methyltransferases* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria* / metabolism
  • Mitochondria* / pathology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Up-Regulation

Substances

  • Methyltransferases
  • METTL1 protein, human
  • Transcription Factors