PEAR1 Promotes Glucose Metabolism Reprogramming in Sepsis-Associated Acute Lung Injury via AARS1-Mediated HIF-1α Lactylation.

Sepsis-associated acute lung injury (S-ALI), in which pulmonary microvascular endothelial cells act as key drivers of disease progression by increasing vascular permeability and ultimately exacerbating lung injury, is associated with a high mortality rate. Here, we report that PEAR1 expression and vascular permeability are increased in the lung tissues of septic mice. Pear1 knockdown markedly reduces pulmonary vascular permeability and consequently attenuates lung injury in septic mice. Mechanistically, PEAR1 promotes the AARS1-mediated lactylation of HIF-1α, primarily at lysine 172 (K172). This lactylation event, in turn, increases the affinity of HIF-1α for importin α, thereby facilitating HIF-1α nuclear translocation. Importantly, HIF-1α K172 lactylation promotes glycolysis, and glycolysis-derived lactate further drives H3K18 lactylation. In addition, this lactate-dependent histone modification is enriched at the Pear1 promoter, resulting in further increases in glycolysis and pulmonary vascular permeability. In vivo, both Pear1 knockout and the targeted delivery of Pear1 siRNA to inflammatory vascular endothelial cells using E-selectin-binding peptide-modified liposomes ameliorate ALI, and improve survival in mice with polymicrobial sepsis. Our study identifies K172 as a previously unreported lactylation site on HIF-1α and shows that PEAR1 promotes AARS1-mediated HIF-1α lactylation, enhances glycolysis, and increases H3K18la enrichment at the Pear1 promoter, thereby forming a positive feedback loop.