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

Area of Science:

• Nephrology
• Molecular Biology
• Immunology

Background:

• Sepsis-induced acute kidney injury (SAKI) is a major cause of kidney dysfunction.
• Long non-coding RNA MALAT1's role in SAKI pathogenesis is not well understood.
• Investigating the molecular mechanisms underlying SAKI is crucial for therapeutic development.

Purpose of the Study:

• To elucidate the role of the METTL3/MALAT1 axis in sepsis-induced acute kidney injury.
• To investigate the underlying molecular mechanisms involving m6A modification and pyroptosis.
• To explore the potential of targeting the METTL3/MALAT1 axis for SAKI treatment.

Main Methods:

• Established a lipopolysaccharide (LPS)-induced SAKI mouse model and cell culture system.
• Manipulated METTL3 and MALAT1 expression using lentiviral vectors.
• Assessed pyroptosis, inflammation, and m6A modification using molecular and cellular assays including MeRIP-qPCR, ELISA, and Western blotting.

Main Results:

• LPS treatment upregulated METTL3 and MALAT1, enhancing MALAT1 m6A modification.
• METTL3 knockdown attenuated pyroptosis and inflammation markers in SAKI.
• METTL3 directly binds to MALAT1, indicating a functional axis that drives pyroptosis in SAKI.

Conclusions:

• METTL3 promotes pyroptosis in SAKI by enhancing MALAT1 m6A modification.
• The METTL3/MALAT1 axis is a key driver of renal inflammation and cell death in SAKI.
• Targeting the METTL3/MALAT1 pathway presents a promising therapeutic strategy for SAKI.