Lactate-mediated lactylation in human health and diseases: Progress and remaining challenges
Xueting Hu, Xiaofeng Wu, Jinyi Xu, Xiang Xu
Abstract
Lactylation is an epigenetic process catalyzed by HATs or AARS1/2 (“writers”) and removed by HDACs (“erasers”). The substrates of lactylation include both histone and non-histone proteins. Histone lactylation typically regulates the transcription of downstream genes, while non-histone lactylation may have multiple effects, influencing the stability, localization, structure, interaction, or function of proteins. Due to lactylation, lactate has transformed from an “ugly duckling”into a “beautiful swan”. In this review, we summarize the roles and mechanisms of lactylation in human health and disease, as well as the remaining questions regarding lactylation. • Because of lactylation, lactate has gracefully transformed from an “ugly duckling” into a “beautiful swan.” • Lactate-mediated lactylation participates in the regulation of numerous physiological and pathological processes. • Histone lactylation alters the transcription of target genes, while nonhistone lactylation has diverse effects on proteins. • Lactylation can be targeted for diseases treatment in two ways: ① by targeting the production or transport of lactate and ② by targeting “writers” or “erasers” of lactylation. • Despite the significant progress made in the research of lactylation, there are still numerous challenges and issues that remain. Lactate was once considered as metabolic waste for a long time. In 2019, Professor Zhao Yingming’s team from the University of Chicago found that lactate could also be used as a substrate to induce histone lactylation and regulate gene expression. Since then, researchers have discovered that lactate-mediated lactylation play important regulatory roles in various physiological and pathological processes. In this review, we aim to discuss the roles and mechanisms of lactylation in human health and diseases, as well as the effects of lactylation on proteins and metabolic modulators targeting lactylation. In this work, we emphasize the crucial regulatory roles of lactylation in the development of numerous physiological and pathological processes. Of relevance, we discuss the current issues and challenges pertaining to lactylation. This review provides directions and a theoretical basis for future research and clinical translation of lactylation.