Lactate attenuates hepatic ischemia-reperfusion injury by reducing intrahepatic inflammation and suppressing hepatocyte-neutrophil interaction via the IL-33/ST2 pathway

Hepatic ischemia-reperfusion injury (HIRI) is a critical contributor to adverse clinical outcomes and increased mortality after liver surgery or transplantation. Lactate, formerly regarded as a metabolic waste product, has emerged as a critical immunomodulatory molecule. This study investigated how lactate modulates HIRI by regulating intrahepatic inflammation and intercellular communication. A mouse model of HIRI was constructed, along with in vitro hypoxia/reoxygenation (H/R) of primary hepatocytes and LPS-stimulated bone marrow-derived neutrophils, to evaluate the protective effects of sodium lactate. RNA sequencing was performed to identify changes in transcriptional profiles induced by lactate pretreatment and to explore regulatory mechanisms involving hepatocytes and neutrophils during HIRI. Cell-cell interaction analysis was performed to identify key interactions by which lactate regulates hepatocyte-neutrophil communication. Furthermore, analysis of transcription factor binding motifs using the JASPAR database was conducted to elucidate potential molecular mechanisms underlying the previously identified key interactions. Lactate administration significantly alleviated hepatic inflammation and tissue injury in HIRI mice. Transcriptomic analysis revealed that lactate attenuated hepatocyte-mediated inflammatory responses, chemotaxis, and apoptosis, while also suppressing neutrophil-driven inflammation, migration, oxidative stress, and NET formation. Integrated digital spatial profiling (DSP) combined with cell-cell interaction analysis revealed IL-33/ST2 as a critical ligand-receptor pair mediating hepatocyte-neutrophil crosstalk, which was significantly downregulated by lactate. IL-33 has been demonstrated to stimulate neutrophil activation and exacerbate liver inflammation via its receptor ST2 in HIRI. Consistently, lactate pretreatment suppressed this pathway, thereby mitigating hepatic injury and intrahepatic inflammation. Mechanistically, lactate inhibited IL-33 expression in hepatocytes via the AKT/c-Fos signaling axis and reduced ST2 expression in neutrophils through the JAK/STAT3 pathway. Lactate alleviates HIRI by protecting hepatocytes, suppressing neutrophil-driven inflammation, and disrupting hepatocyte-neutrophil communication through the IL-33/ST2 axis.