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Lactate-Primed NETosis Modulates Hepatic Regeneration During Acute Liver Failure via the TLR9/KLF15/AJUBA Axis
Jin Guo1, Xiaoya Zhang1, Danmei Zhang1
1Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China.
Cell Proliferation
|June 22, 2026
Summary
Lactate accumulation in acute liver failure triggers neutrophil extracellular traps (NETs). This process, involving Kupffer cells and hepatocytes, inhibits liver regeneration via the TLR9/KLF15/AJUBA pathway, offering new therapeutic targets.
Area of Science:
- Hepatology
- Immunology
- Metabolic Signaling
Background:
- Acute liver failure (ALF) involves massive hepatocyte death and impaired regeneration.
- The metabolic and immune interactions driving ALF pathology are not fully understood.
Purpose of the Study:
- To investigate the role of metabolic-immune crosstalk in ALF.
- To identify the mechanisms by which liver regeneration is suppressed during ALF.
Main Methods:
- Integrated RNA-sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) analyses.
- Investigated lactate's role in neutrophil extracellular trap (NETs) formation.
- Utilized macrophage depletion and monocarboxylate transporter 1 (MCT1) inhibition.
- Examined Toll-like receptor 9 (TLR9) and Krüppel-like factor 15 (KLF15) signaling pathways.
Main Results:
- Kupffer cells reprogram metabolism, accumulating lactate in ALF.
- Lactate promotes NETosis via MCT1 in neutrophils, exacerbating liver injury.
- Hepatocytes internalize NETs DNA, activating TLR9, which suppresses KLF15.
- KLF15 downregulation disrupts AJUBA interaction, inhibiting hepatocyte proliferation via YAP1.
Conclusions:
- Lactate-driven NETosis by Kupffer cells and neutrophils impairs liver regeneration in ALF.
- The TLR9/KLF15/AJUBA axis is a key pathway mediating regenerative failure.
- Targeting this crosstalk presents potential therapeutic strategies for ALF.
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