MALAT1’s m6A Modification by METTL3 Promotes Pyroptosis and Inflammation in Sepsis-Induced Acute Kidney Injury in Mice

Pengwei Guo,1,* Gao Deng,1,* Lingling Li,1 Haidong Wei,1 Yunxia Gong,1 Yanhong Tan,1 Yanfei Ma2 1Department of Nephrology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise City, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Glandular Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise City, Guangxi Zhuang Autonomous Region, People’s Republic of China*These authors have contributed equally to this workCorrespondence: Yanfei Ma, Department of Glandular Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, No. 18, Zhongshan 2nd Road, Baise City, Guangxi Zhuang Autonomous Region, People’s Republic of China, Email yanfei.ma@ymun.edu.cnBackground: Sepsis-induced acute kidney injury (SAKI) significantly contributes to renal dysfunction. Long non-coding RNA MALAT1 has been implicated in regulating inflammation and cell death in various diseases. However, its role in SAKI and the underlying mechanisms remain unclear.Methods: A lipopolysaccharide (LPS)-induced SAKI mouse model and LPS-treated TCMK-1 cells were established. METTL3 and MALAT1 were manipulated via lentiviral-mediated knockdown or overexpression. m6A RNA levels were measured using MeRIP-qPCR, while pyroptosis and inflammation were assessed through ELISA, flow cytometry, Western blotting, immunohistochemistry, and immunofluorescence. RNA immunoprecipitation was conducted to confirm the interaction between METTL3 and MALAT1.Results: LPS treatment significantly increased METTL3 and MALAT1 expression and enhanced m6A modification of MALAT1. METTL3 knockdown reduced pyroptosis markers (cleaved GSDMD, Caspase-1, and NLRP3) and inflammatory cytokines (IL-1β and IL-18), while MALAT1 overexpression partially reversed these effects. RIP confirmed that METTL3 binds directly to MALAT1. In vivo and in vitro experiments demonstrated that the METTL3/MALAT1 axis contributes to pyroptosis in SAKI.Conclusion: METTL3 promotes pyroptosis in SAKI by enhancing the m6A modification of MALAT1. Targeting the METTL3/MALAT1 axis may provide a potential therapeutic strategy for SAKI by mitigating renal inflammation and cell death.Keywords: sepsis-induced acute kidney injury, METTL3, MALAT1, pyroptosis