MALAT1's m(6)A Modification by METTL3 Promotes Pyroptosis and Inflammation in Sepsis-Induced Acute Kidney Injury in Mice.

BACKGROUND: 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 m(6)A 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.