KAT8-mediated epigenetic modifications: Physiological functions, heterogeneity in disease, and advances in targeted development

Abstract

Summary KAT8 (MOF/MYST1) is a core histone acetyltransferase of the MYST family. Beyond its canonical H4K16ac activity, KAT8 catalyzes diverse acylations and regulates stem cell biology, DNA repair, metabolism, and immunity. This review systematically integrates KAT8’s regulatory networks across physiology and disease. We decipher the molecular basis of its context-dependent “double-edged sword” role in cancer, acting predominantly as an oncoprotein yet exhibiting tumor-suppressive functions under specific conditions. We evaluate current KAT8 inhibitor development, from early non-selective compounds to selective leads, and highlight persistent translational hurdles including insufficient specificity and limited in vivo efficacy. This work provides a comprehensive framework that clarifies recent controversies—such as whether H4K16ac primarily governs transcription or replication timing, and which KAT8-containing complex catalyzes, which acetylation mark—and establishes a rationale for future precision-targeting strategies and biomarker development grounded in KAT8 functional heterogeneity.