Ubiquitous protein lactylation in health and diseases

Abstract For decades, lactate has been considered a byproduct of glycolysis. The lactate shuttle hypothesis shifted the lactate paradigm, demonstrating that lactate not only plays important roles in cellular metabolism but also cellular communications, which can transcend compartment barriers and can occur within and among different cells, tissues and organs. Recently, the discovery that lactate can induce a novel post-translational modification, named lysine lactylation (Kla), brings forth a new avenue to study nonmetabolic functions for lactate, which has inspired a ‘gold rush’ of academic and commercial interest. Zhang et al. first showed that Kla is manifested in histones as epigenetic marks, and then mounting evidences demonstrated that Kla also occurs in diverse non-histone proteins. The widespread Kla faithfully orchestrates numerous biological processes, such as transcription, metabolism and inflammatory responses. Notably, dysregulation of Kla touches a myriad of pathological processes. In this review, we comprehensively reviewed and curated the existing literature to retrieve the new identified Kla sites on both histones and non-histone proteins and summarized recent major advances toward its regulatory mechanism. We also thoroughly investigated the function and underlying signaling pathway of Kla and comprehensively summarize how Kla regulates various biological processes in normal physiological states. In addition, we also further highlight the effects of Kla in the development of human diseases including inflammation response, tumorigenesis, cardiovascular and nervous system diseases and other complex diseases, which might potentially contribute to deeply understanding and interpreting the mechanism of its pathogenicity. Graphical Abstract