Abstract DP040: Lactate-Triggered Transient receptor potential vanilloid 1 (TRPV1)-p300 Signaling Mediates Neuronal Proinflammatory Activation in Ischemic Stroke through Histone H3K18 Lactylation (H3K18la)

Objectives: Ischemia-induced lactate accumulation contributes to neuronal injury. However, the mechanisms linking metabolic stress to epigenetic regulation and neuroinflammation remain unclear. This study investigates how lactate triggers neuronal damage via histone lactylation, with a focus on the TRPV1–p300–H3K18la signaling pathway. Methods: Male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (tMCAO) with or without TRPV1 or p300 inhibition. Infarct volume, neurological deficits, lactate levels, histone lactylation, proinflammatory gene expression, ATP production, and mitochondrial integrity were assessed. In SH-SY5Y neurons subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), lactate stimulation, gene knockdown, and pharmacologic inhibition were used to probe TRPV1 activation, Ca 2+ influx, H3K18la enrichment (ChIP-qPCR), and cytokine expression. Results: Lactate levels rose rapidly following ischemia, inducing TRPV1 membrane translocation (3.7 ± 0.3-fold vs. Sham, p