2. Academic Validation
  3. Inhibition of N6-methyladenosine methylation of ASC by berberine ameliorates pyroptosis of renal tubular epithelial cells in acute kidney injury

Inhibition of N6-methyladenosine methylation of ASC by berberine ameliorates pyroptosis of renal tubular epithelial cells in acute kidney injury

  • Cell Signal. 2025 Mar 11:131:111732. doi: 10.1016/j.cellsig.2025.111732.
Jiacheng Li 1,  Linxiao Lv 1,  Mingyang Hu 1,  Zhangsuo Liu 2,  Sijie Zhou 3
Affiliations

Affiliations

  • 1 Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China; Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, PR China; Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University Zhengzhou, Henan, China; Innovation Center of Basic Research for Metabolic-Associated Fatty Liver Disease, Ministry of Education of, China.
  • 2 Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China; Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, PR China; Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University Zhengzhou, Henan, China; Innovation Center of Basic Research for Metabolic-Associated Fatty Liver Disease, Ministry of Education of, China. Electronic address: zhangsuoliu@zzu.edu.cn.
  • 3 Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China; Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, PR China; Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University Zhengzhou, Henan, China; Innovation Center of Basic Research for Metabolic-Associated Fatty Liver Disease, Ministry of Education of, China. Electronic address: fcczhousj@zzu.edu.cn.
PMID: 40074191 DOI: 10.1016/j.cellsig.2025.111732
Abstract

Acute kidney injury (AKI) lacks a definitive therapeutic approach beyond supportive care. One significant pathological mechanism involves the regulated death of tubular epithelial cells; however, the regulatory mechanisms underlying this cell death pathway require further investigation. The N6-methyladenosine (m6A) modification, recognized as the most prevalent modification in eukaryotes, plays a critical role in the regulatory processes associated with AKI. Here, this study investigates the association between methyltransferase-like 3 (METTL3) and Pyroptosis in mice with folic acid (FA)-induced AKI. Both in vitro and in vivo experiments have confirmed that METTL3 plays a role in AKI progression, correlating with renal epithelial cell Pyroptosis and inflammation. Moreover, RNA immunoprecipitation quantitative PCR (RIP-qPCR) analysis demonstrated that METTL3-mediated m6A methylation occurred in the mRNA of Apoptosis-associated speck-like protein containing a CARD (ASC) in H2O2-induced renal tubular epithelial (TCMK-1) cells. Notably, METTL3 knockdown resulted in reduced ASC protein expression, decreased release of inflammatory factors, and reduced Pyroptosis. In addition, we verified the inhibitory effect of berberine hydrochloride, a monomer used in traditional Chinese medicine, on METTL3 expression. We also demonstrated that berberine ameliorated FA-induced AKI and H2O2-induced Pyroptosis in TCMK-1 cells by inhibiting METTL3 and modulating the ASC/Caspase-1/Gasdermin D axis. These findings provide insights into targeted therapies and drug development for AKI.

Keywords

ASC; Acute kidney injury; Berberine; METTL3; Pyroptosis; m6A methylation.

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