DLGAP5 Promotes Acute Liver Injury via Hepatocyte Pyroptosis-Driven Macrophage Metabolic Reprogramming and M1...

Area of Science:

• Molecular Biology
• Immunology
• Hepatology

Background:

• Pyroptosis is a programmed cell death pathway implicated in inflammatory diseases.
• Methyltransferase-like 3 (METTL3) is crucial for N6-methyladenosine (m6A) modification and cell fate regulation.
• The role of pyroptosis and m6A modification in acute liver injury (ALI) remains unclear.

Purpose of the Study:

• To investigate the role of pyroptosis in ALI.
• To elucidate the involvement of METTL3-mediated m6A modification in ALI pathogenesis.
• To identify molecular targets and intercellular communication pathways in ALI.

Main Methods:

• Construction of Mettl3 mutant and Nlrp3 knockout mice.
• Establishment of CCl₄- and TAA-induced ALI models.
• Evaluation of pyroptosis and m6A modification using cell assays, MeRIP-seq, and molecular analyses.

Main Results:

• Hepatocyte pyroptosis is a hallmark of ALI, with upregulated METTL3-mediated m6A modification.
• METTL3 targets DLGAP5, promoting pyroptosis via NLRP3 inflammasome activation and exacerbating ALI.
• Pyroptotic hepatocytes activate macrophages, worsening ALI; inhibiting DLGAP5 or hepatocyte-macrophage interaction shows therapeutic promise.

Conclusions:

• METTL3-mediated m6A modification drives pyroptosis and ALI progression through DLGAP5.
• Intercellular communication between hepatocytes and macrophages is critical in ALI pathogenesis.
• Targeted inhibition of DLGAP5 and blocking hepatocyte-macrophage crosstalk are potential ALI treatment strategies.