p300: expanding beyond acetylation to mastermind lactylation-dependent tumorigenesis.

The transcription coactivator p300 is canonically recognized as a histone acetyltransferase that orchestrates chromatin remodeling and gene expression. However, recent breakthroughs have expanded the catalytic landscape of p300 beyond acetylation to include lactylation, a metabolic stress induced modification driven by lactate accumulation. As a principal lactyl-transferase, p300 acts as a sensor of the Warburg effect, directly translating cellular metabolic status into epigenetic regulation. This catalytic duality extends beyond histones to non-histone substrates, profoundly impacting tumor progression, immune evasion, and metabolic adaptation. This review synthesizes the established roles of p300 in acetylation while critically examining its emerging identity as a writer of protein lactylation. By highlighting the competitive interplay between acetyl-CoA and lactyl-CoA usage, we position p300 as a central integrator that couples metabolic signaling with transcriptional reprogramming in cancer and other pathological states. Furthermore, this review bridges the gap between mechanistic discovery and clinical translation by evaluating the therapeutic potential of targeting p300 lactyl-transferase activity. We highlight the emerging clinical relevance of p300 inhibitors, such as CCS1477 (in Phase I/II trials) and the preclinical agent A-485, discussing how these compounds, originally designed for acetylation or bromodomain inhibition, may be repurposed to dismantle lactylation-driven oncogenic networks and overcome metabolic immune evasion in refractory tumors.