p300-Mediated Histone H3K18 Lactylation Promotes Mitochondrial ROS Accumulation via Mitophagy Inhibition to Potentiate Dopamine Agonists Efficacy in Prolactinomas [CUT&Tag]

Prolactinomas are the most common functional pituitary adenomas, with dopamine receptor agonists (DAs) as the first-line therapy. However, 10–30% of patients develop DA resistance, and the underlying mechanisms remain incompletely elucidated.Clinical samples were collected to analyze p300 expression. Experiments including immunofluorescence, immunohistochemistry, gene editing, Western blot, co-immunoprecipitation, ChIP-qPCR, RNA/CUT&Tag sequencing, flow cytometry, Seahorse assay, and mass spectrometry were performed to explore the synergistic anti-tumor mechanism of upregulating/activating p300 combined with DAs. DAs downregulated p300 by inhibiting the cAMP-PKA-CREB pathway. Upregulating/activating p300 synergized with DAs to promote mitochondrial ROS elevation and cell apoptosis, which depends on p300’s histone acetyltransferase (HAT) domain mediating histone H3 lysine 18 lactylation (H3K18la). p300-mediated H3K18la significantly promoted intracellular ROS accumulation by upregulating Ndufs7 (promoting mitochondrial ROS production) and Washc1 (inhibiting mitophagy). YF-2, a p300 HAT domain activator, exhibited synergistic anti-tumor activity with DAs.This study reveals the p300-H3K18la- mitophagy-ROS regulatory axis, providing a new target and strategy for treating DA-resistant prolactinomas.