Epigenetic ‘language’ of histone lysine: a promising target for macrophage-driven inflammation

Epigenetic modification in inflammation remains a frontier field with many unanswered questions. Macrophages, as the core cells that maintain tissue homeostasis and regulate inflammation, possess functional plasticity that enables their switching between pro‑inflammatory and anti‑inflammatory states. This plasticity is primarily regulated by epigenetic mechanisms. How histone lysine modifications, a core epigenetic regulatory mechanism, regulate the phenotypic transition of macrophages during inflammation therefore remains a key area of research. This review synthesizes current research on how histone lysine modifications, such as crotonylation, lactylation, ubiquitination, methylation, succinylation, and acetylation, act as key molecular switches to reshape chromatin architecture and regulate gene expression during macrophage activation. Furthermore, this review systematically delineates the mechanistic pathways through which these epigenetic changes coordinate inflammatory signaling cascades within complex regulatory networks. Deciphering this complex epigenetic ‘language’ provides a theoretical foundation and deeper insights into the therapeutic intervention of macrophage-driven inflammation, potentially leading to more precise treatment strategies for inflammatory diseases.