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Here, we demonstrate that lactate acts as a pivotal signal that triggers neutrophil extracellular traps (NETs) formation and release. Integrated RNA\u2010seq and scRNA\u2010seq 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\u2010like receptor 9 (TLR9). Activation of the TLR9 signalling pathway suppresses the expression of Kr\u00fcppel\u2010like factor 15 (KLF15). This downregulation diminishes AJUBA and disrupts the KLF15\u2010AJUBA interaction, thereby increasing the phosphorylation of YAP1 and impeding hepatocyte proliferation. Notably, KLF15 overexpression bypassed TLR9\u2010mediated inhibitory signals and rescued the NETs\u2010induced regenerative failure in\u00a0vitro. In conclusion, our study elucidates a novel KCs\u2010neutrophil\u2010hepatocyte crosstalk wherein lactate\u2010driven NETosis thwarts liver regeneration via the TLR9\/KLF15\/AJUBA axis, thereby identifying potential therapeutic targets for the clinical management of ALF.<\/jats:p>","DOI":"10.1111\/cpr.70251","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T23:19:35Z","timestamp":1782170375000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lactate\u2010Primed\n                    <scp>NETosis<\/scp>\n                    Modulates Hepatic Regeneration During Acute Liver Failure via the\n                    <scp>TLR9<\/scp>\n                    \/\n                    <scp>KLF15<\/scp>\n                    \/\n                    <scp>AJUBA<\/scp>\n                    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