A review article recently published in Molecular Biomedicine by Prof. Juan Du and Dr. Xia Peng of Capital Medical University School of Stomatology presents an authoritative and up-to-date synthesis of the molecular biology of lysine lactylation (Kla), a novel post-translational modification that connects cellular metabolism with gene expression and protein function.
First described in 2019, Kla is now known to modify not only histones but also a vast array of non-histone proteins. These modifications regulate processes such as inflammation, DNA repair, cancer metabolism, and immune signaling. While histone Kla has been the primary focus of earlier research, this new review not only summarizes histone lactylation but also systematically dissects the molecular mechanisms, functional roles, and therapeutic implications of non-histone Kla for the first time, marking a critical shift in the field.
"Our main goal was to bridge the gap between histone-centric studies and the growing evidence of non-histone protein lactylation," the authors state. "We believe the Kla axis represents an underexplored but highly promising frontier in epigenetics, immunology, and cancer biology."
The review systematically categorizes and compares the characteristics of histone and non-histone lactylation. Over the past few years, histone Kla, particularly at key sites such as H3K18la, H3K23la, and H4K12la, has been shown to participate in vital biological processes, including early embryo development, immune responses, metabolic reprogramming, and tumor progression. For example, H3K18la has been implicated in macrophage polarization, pulmonary hypertension, and cancer angiogenesis. Similarly, H4K12la has been associated with oocyte development, tissue repair, and tumor proliferation. In addition to summarizing advances in histone Kla, this review is among the first to systematically dissect the molecular mechanisms, functional roles, and disease relevance of non-histone Kla, marking a critical expansion in the field. The authors compare histone and non-histone Kla in terms of enzyme regulation, substrate specificity, cellular localization, and biological outcomes.
The review emphasizes that non-histone Kla is involved in a diverse range of cellular processes, including autophagy (Vps34-Kla), ferroptosis (Tau-Kla), and immune signaling (RIG-I-Kla, BCAP-Kla). Notably, non-histone Kla can occur through both enzymatic and non-enzymatic pathways, influencing protein function and signaling networks beyond the chromatin level.
The review also provides an updated list of Kla "writers," "erasers," and "readers", as well as novel L-lactyl-CoA synthetases such as ACSS2 and GTPSCS. A dedicated section addresses new detection technologies like CUT&Tag and tandem mass spectrometry, which are enabling site-specific Kla mapping.
While Kla's involvement in cancer has drawn particular attention, Peng and Du's review reveals that its functional spectrum in non-histone proteins is even broader. These functions include links to cardiovascular disease, sepsis, neurodegeneration, and other pathological conditions.
"We hope this work will serve not only as a reference but as a launchpad for further studies on histone and non-histone Kla and its clinical potential," says Du.
By integrating histone and non-histone lactylation, this review opens new directions for investigating how metabolism-driven protein modifications reshape cellular behavior and how these pathways can be harnessed in therapy.
See the article:
Histone and non-histone lactylation: molecular mechanisms, biological functions, diseases, and therapeutic targets
https://doi.org/10.1186/s43556-025-00275-6
