Endothelial SP1 lactylation promotes bronchopulmonary dysplasia via regulation of Cdkn1a expression

Bronchopulmonary dysplasia (BPD) is a major complication of prematurity, and endothelial dysfunction contributes to its pathogenesis. Although lactate metabolism is dysregulated in BPD, whether lactate-derived lysine lactylation contributes to endothelial dysfunction remains unknown. This study investigated the role of lactylation in endothelial injury and the involvement of SP1-Cdkn1a axis in BPD. We found that lactate levels and global lactylation levels were increased in both in vitro and in vivo models of BPD, accompanied by impaired endothelial proliferation, migration and angiogenic capacity. Integrated bioinformatic analysis identified Cdkn1a as a glycolysis-associated hub gene in BPD, and its upregulation in pulmonary vascular endothelial cells (PVECs) was confirmed experimentally. Subsequent Cdkn1a knockdown alleviated hyperoxia-induced endothelial dysfunction. In addition, inhibition of glycolysis reduced lactylation level in PVECs, suppressed Cdkn1a expression, and partially improved pulmonary microvascular injury. To explore the upstream mechanism, lactylome profiling identified SP1, a known transcription factor of Cdkn1a, as a lactylated candidate. Increased SP1 lactylation and enhanced binding at the Cdkn1a promoter were verified in PVECs from BPD mice. K640R mutation attenuated SP1-dependent Cdkn1a promoter activation. Overall, this study reveals the involvement of endothelial lactylation in pathogenesis of BPD and implicates the SP1-Cdkn1a axis as a potential therapeutic target.