METTL1 aggravates sepsis-acute kidney injury by promoting m7G methylation of NLRP3-mediated pyroptosis

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Wang-40-2025-2034-2025.pdf(4.56 MB)
Date
2025
Authors
Yuexuan Chen
Ming Fang
Jingjing Hu
Lu Wang
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Abstract
Sepsis is a major cause of acute kidney injury (AKI). Dysregulation of N7-methyladenosine (m7G) methylation is a pathogenic mechanism of sepsis. However, the role of m7G methylation in renal damage remains poorly understood. In this study, we investigated the regulation of METTL1, an m7G "writer", on pyroptosis in sepsis-induced AKI. HK-2 cells were treated with lipopolysaccharide (LPS), and pyroptosis was assessed using enzyme-linked immunosorbent assays and western blotting. The m7G methylation status of NLRP3 was analyzed through methylated-RNA immunoprecipitation (Me-RIP), RNA immuno-precipitation (RIP), and dual-luciferase reporter assays. Renal injury in mice subjected to cecal ligation and puncture (CLP) was evaluated using hematoxylin and eosin (H&E) staining. Our results demonstrated that METTL1 expression was significantly upregulated in both LPS-treated HK-2 cells and the CLP-induced mouse model. Interfering with METTL1 suppressed LPS-induced pyroptosis in vitro and attenuated kidney damage and pyroptosis in vivo. Furthermore, METTL1 knockdown inhibited m7G methylation of NLRP3, thereby reducing its stability. Overexpression of NLRP3 abrogated the inhibition of pyroptosis caused by METTL1 knockdown. In conclusion, silencing of METTL1 alleviates sepsis-induced AKI by inhibiting m7G methylated NLRP3-mediated pyroptosis in renal tubular epithelial cells. These findings suggest that targeting METTL1 may represent a promising therapeutic strategy for managing sepsis-associated AKI.
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Kidney injury , m7G methylation , METTL1 , Pyroptosis , NLRP3 , Sepsis
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http://hdl.handle.net/10201/172149
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Histology and histopathology, Vol.40, Nº12, (2025)
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