Lactate and lactylation: mechanisms, function, diseases, and therapeutic targets

The paradigm shift of lactate from a mere metabolic byproduct to a pleiotropic signaling molecule, coupled with the discovery of lactylation, provides a crucial framework for understanding how metabolic reprogramming drives systemic pathology. In this review, we systematically delineate the dynamic equilibrium of lactate homeostasis and the evolution of the lactate shuttle theory, exploring its multidimensional roles as a metabolic substrate, signal transducer, and immunomodulator. Furthermore, we summarize how lactylation orchestrates diverse pathophysiological processes across major organ systems, including metabolic dysfunction and fibrosis in the cardiovascular system, neuroinflammation and apoptosis in the central nervous system, and microenvironment-driven injury across the respiratory, digestive, and urinary tracts. Notably, we highlight the female reproductive system as a unique physiological model for investigating metabolic-epigenetic crosstalk, detailing how histone and non-histone lactylation contribute to the progression of various gynecological pathologies and critical reproductive processes. Finally, we evaluate the clinical translational potential of lactate-related biomarkers and lactylation-targeted therapeutics. Ultimately, this comprehensive framework underscores lactate and its mediated modifications as fundamental epigenetic regulators of cellular function and promising pharmacological targets for precision medicine.