H3K18 lactylation promotes VEGFR-3-dependent lymphatic hyperplasia and barrier disruption in metabolic syndrome

The epigenetic mechanisms by which nutrient overload reprograms lymphatic endothelial cells (LECs) remain unclear. Here we show that metabolic stress drives LECs into a glycolytic state, producing lactate that fuels EP300-catalyzed histone H3K18 lactylation at the VEGFR-3 promoter, thereby enhancing chromatin accessibility and VEGFR-3 transcription. This epigenetically induced VEGFR-3 not only promotes LEC proliferation but also engages αVβ1 integrin to activate Src signaling, triggering VE-cadherin internalization and barrier disruption. In mice with metabolic syndrome, this axis drives collecting lymphatic hyperplasia with overt junctional disruption, leading to impaired cardiac lymphatic drainage, myocardial edema, and diastolic dysfunction, a pathological phenotype recapitulated in cardiac lymphatic vessels of metabolic syndrome patients. Genetic ablation of VEGFR-3 in LECs or pharmacological inhibition of lactate production with FX-11 restores lymphatic junctional integrity, improves cardiac drainage, and alleviates myocardial edema. Collectively, these findings establish H3K18 lactylation as a metabolic-epigenetic switch that uncouples lymphatic growth from barrier function under nutrient overload, and identify the LDHA-lactate-H3K18la-VEGFR-3 axis as a targetable node for lymphatic dysfunction in metabolic disease.