Lactylation in health and disease: physiological or pathological?

Lactate is an indispensable substance in various cellular physiological functions and plays regulatory roles in different aspects of energy metabolism and signal transduction. Lactylation (Kla), a key pathway through which lactate exerts its functions, has been identified as a novel posttranslational modification (PTM). Research indicates that Kla is an essential balancing mechanism in a variety of organisms and is involved in many key cellular biological processes through different pathways. Kla is closely related to disease development and represents a potential and important new drug target. In line with existing reports, we searched for newly discovered Kla sites on histone and nonhistone proteins; reviewed the regulatory mechanisms of Kla (particularly focusing on the enzymes directly involved in the reversible regulation of Kla, including "writers" (modifying enzymes), "readers" (modification-binding enzymes), and "erasers" (demodifying enzymes); and summarized the crosstalk between different PTMs to help researchers better understand the widespread distribution of Kla and its diverse functions. Furthermore, considering the "double-edged sword" role of Kla in both physiological and pathological contexts, this review highlights the "beneficial" biological functions of Kla in physiological states (energy metabolism, inflammatory responses, cell fate determination, development, etc.) and its "detrimental" pathogenic or inducive effects on pathological processes, particularly malignant tumors and complex nontumor diseases. We also clarify the molecular mechanisms of Kla in health and disease, and discuss its feasibility as a therapeutic target. Finally, we describe the detection technologies for Kla and their potential applications in diagnosis and clinical settings, aiming to provide new insights for the treatment of various diseases and to accelerate translation from laboratory research to clinical practice.