Lactylation and macrophage polarization from a clinical perspective: pathological mechanisms and therapeutic...

As an emerging epigenetic modification, lactylation has attracted increasing attention in studies of macrophage activation in recent years. Accumulating evidence indicates that lactylation not only regulates macrophage gene-expression programs and polarization trajectories, but also contributes to the pathogenesis and prognosis of a wide range of diseases. In this review, we summarize fundamental concepts related to lactate metabolism and protein lactylation, and we discuss how lactylation shapes macrophage function and plasticity, with particular emphasis on its mechanistic roles under distinct pathophysiological conditions. In addition, we examine the regulatory networks through which lactylation modulates macrophage polarization and highlight its potential translational applications in clinical intervention. Collectively, this review aims to provide updated insights and therapeutic perspectives to support disease prevention, delay progression, and improve patient outcomes. We also emphasize the limitations of causal inference in current studies, contextualize the classical M1/M2 nomenclature, and synthesize how lactate flux, microenvironmental cues, thresholds of lactylation, and writer/eraser/reader balance may determine divergent disease outcomes.