Lactylation of BCAT2-K377 Contributes to the Progression of Severe Preeclampsia

BACKGROUND: Preeclampsia is a pregnancy-specific disorder characterized by placental hypoxia and superficial invasion of trophoblast cells. However, the precise mechanisms by which hypoxia induces lactate and lactylation remain unclear. METHODS: Pan lysine lactylation levels were analyzed in the placentae of 36 patients with severe preeclampsia (sPE) and 36 normotensive pregnancies. A global lactylome analysis was performed, and branched-chain amino acid transaminase 2-lysine 377 (BCAT2-K377) was selected for further investigation. The BCAT2 mutant with lysine 377 mutated to arginine (BCAT2-377R) was constructed to evaluate the effect on trophoblast migration, invasion, tube formation, and oxidative stress. The impact of the BCAT2-377R mutant on BCAT2 ubiquitination and degradation was further examined using MG132 and cycloheximide supplementation. Co-immunoprecipitation and double-immunofluorescence staining were conducted to identify the lactyltransferase of BCAT2. The specialized antibody was developed to validate branched-chain amino acid transaminase 2-lysine 377 lactylation (BCAT2-K377la) abundance in tissues and treated cells. A preeclampsia-like rat model was constructed to further verify whether the results were consistent with the clinical findings. RESULTS: Lactylation levels were elevated in the placentae of sPE. High lactate concentration enhanced Pan lysine lactylation and reduced BCAT2 protein levels while inhibiting cell migration, invasion, and tube formation. BCAT2-K377la impaired cell biological behaviors, increased oxidative stress, and promoted BCAT2 ubiquitination. The EP300 lysine acetyltransferase (p300) acted as a lysine lactylation writer of BCAT2. BCAT2-K377la abundance was upregulated in sPE placentae and cells treated with hypoxia and lactate. In the rat model, elevated placental Pan lysine lactylation and BCAT2-K377la levels mirrored findings in clinical samples. CONCLUSIONS: Our findings emphasized the role of nonhistone lactylation in sPE pathogenesis. Targeting BCAT2-K377la may serve as a potential intervention strategy for sPE.