Lactate‐Primed NETosis Modulates Hepatic Regeneration During Acute Liver Failure via the TLR9 / KLF15

ABSTRACT

Acute liver failure (ALF) is characterised by massive hepatocyte death and compromised regenerative capacity, yet the metabolic‐immune crosstalk underlying these pathological processes remains poorly understood. Here, we demonstrate that lactate acts as a pivotal signal that triggers neutrophil extracellular traps (NETs) formation and release. Integrated RNA‐seq and scRNA‐seq analyses revealed profound glycolytic reprogramming in Kupffer cells (KCs) during ALF, leading to lactate accumulation within the hepatic microenvironment. Mechanistically, neutrophils import exogenous lactate into mitochondria via monocarboxylate transporter 1 (MCT1), which subsequently activates NETosis. Macrophage depletion or administration of an MCT1 inhibitor reduced NETs formation and ameliorated liver injury. Furthermore, we demonstrate that hepatocytes internalise NETs DNA, which is sensed by endosomal Toll‐like receptor 9 (TLR9). Activation of the TLR9 signalling pathway suppresses the expression of Krüppel‐like factor 15 (KLF15). This downregulation diminishes AJUBA and disrupts the KLF15‐AJUBA interaction, thereby increasing the phosphorylation of YAP1 and impeding hepatocyte proliferation. Notably, KLF15 overexpression bypassed TLR9‐mediated inhibitory signals and rescued the NETs‐induced regenerative failure in vitro. In conclusion, our study elucidates a novel KCs‐neutrophil‐hepatocyte crosstalk wherein lactate‐driven NETosis thwarts liver regeneration via the TLR9/KLF15/AJUBA axis, thereby identifying potential therapeutic targets for the clinical management of ALF.