Lactylation of HSP90β disrupts HSP90β-APAF-1 interaction to mediate heat stress induced brain microvascular endothelial cell apoptosis

Lysine lactylation (Kla) is a metabolite-sensing post-translational modification that bridges cellular metabolism to protein function. Here, we discover that heat stress triggers anaerobic glycolysis and lactate accumulation in brain microvascular endothelial cells (BMECs).Mechanistically, AARS1 catalyzes the transfer of lactate to HSP90β at lysine 275 (K275). Critically, this lactylation modification acts as a regulatory switch for the protective factor HSP90β, disrupting its interaction with apoptotic protease-activating factor 1 (APAF-1). This modification thereby compromises the protective function of HSP90β, liberating APAF-1 to activate the mitochondrial apoptosis pathway, resulting in blood-brain barrier (BBB) injury. Functional validation reveals that decreasing lactate production, overexpressing HSP90β lactylation-deficient mutant, or inhibiting AARS1 confers protection. These findings establish HSP90β-K275 lactylation as a metabolic switch that modulates protective mechanisms during heat-stress-induced cerebrovascular injury.