G protein-coupled receptor 87 promotes lung adenocarcinoma progression and metastasis via a histone lactylation-driven glycolytic feed-forward circuit.

Metastatic progression is the leading cause of mortality in lung adenocarcinoma (LUAD), yet how oncogenic signals are translated into stable metabolic and epigenetic programs that sustain tumour progression remains poorly understood. Here, through integrated single-cell, bulk, and spatial transcriptomic analyses, we identify the orphan G protein-coupled receptor GPR87 as a progression-associated regulator linked to enhanced glycolytic activity and adverse clinical outcome in LUAD. Mechanistically, GPR87 activates the cAMP/PKA/CREB pathway to induce acetyl-CoA synthetase 2 (ACSS2) transcription, thereby promoting histone H3 lysine 27 lactylation (H3K27la). H3K27la directly enhances transcription of dihydrolipoamide S-acetyltransferase (DLAT), reinforcing glycolytic flux and lactate production in a self-sustaining metabolic-epigenetic circuit. In parallel, GPR87 physically stabilizes lactate dehydrogenase A (LDHA), further amplifying lactate output. Genetic disruption of ACSS2 suppresses GPR87-driven tumour growth and metastatic colonization in vivo. Consistently, coordinated activation of this axis is enriched in advanced-stage human LUAD. Together, these findings define a GPR87-centered metabolic-epigenetic circuit that sustains glycolytic dominance and supports LUAD progression and metastasis.