The histone acylation network: emerging therapeutic targets for remodeling the epigenetic landscape in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, a status primarily attributable to its intricate molecular circuitry. The histone acylation network serves as a key orchestrator of PDAC progression through epigenetic reprogramming, making its regulatory components high-value targets for groundbreaking therapeutic interventions. Here, we review how diverse histone acylations govern pancreatic cancer biology. We first outline the established roles of acetylation in proliferation, metastasis, and immune evasion. Subsequently, we focus on novel modifications intimately linked to tumor metabolic reprogramming, with a particular emphasis on histone lactylation. We also explore emerging modifications such as succinylation and propionylation as potential therapeutic targets. We further underscore that these diverse acylations exhibit extensive crosstalk, forming an intricate and dynamic regulatory network mediated by shared enzymatic “writers” and “erasers” (e.g., p300, HDACs), and exerting synergistic or antagonistic effects on key genes including MYC and GATA binding protein 6 (GATA6). By providing a comprehensive deciphering of the dysregulated histone acylation network, this review highlights its significant transformative potential. Such understanding not only unveils novel pathogenic drivers of pancreatic tumorigenesis but also establishes a mechanistic foundation for precision oncology. Furthermore, we evaluate the current landscape of clinical trials and discuss the potential of epigenetic agents to sensitize tumors to conventional or targeted therapies. By bridging the gap between complex molecular crosstalk and clinical application, this review aims to provide a practical framework for the rational design of targeted inhibitors and the formulation of synergistic combination therapies to overcome current treatment limitations and therapeutic resistance.