Lactylation: A Modulator of Progression and Therapeutic Responses in Digestive System Cancers and Non-Malignant Liver Diseases

Protein lactylation is an emerging post-translational modification (PTM) driven by the accumulation of lactate in disease states; it serves as a key regulatory mechanism linking cellular metabolism, epigenetics, and immune regulation. The molecular system regulating lactoylation includes “writers”, “erasers” and “readers”. This mechanism has broad implications for both histone and non-histone lactylation and can influence cancer stem cell (CSC) properties as well as the microenvironment of tumors and non-malignant liver diseases by regulating gene transcriptional activity in cancer and non-malignant liver diseases. Recent studies have shown that lactylation promotes immunosuppression and drug resistance, a finding that offers new directions for therapeutic interventions in both cancer and non-malignant liver diseases. Lactylation prominently expressed in digestive system cancers; it is also involved in the pathological processes of non-malignant liver diseases. There are various methods for detecting lactylation, and the potential of its associated biomarkers in disease diagnosis and prognostic assessment has also been highlighted. Currently, many drugs under development are attempting to inhibit the progression of tumors and other diseases by regulating lactylation through targeting lactylation-related markers. However, lactylation has limitations. There is limited research on lactylation “readers” and clinical drugs targeting lactylation, and the lack of unified quantitative standards for lactylation detection still poses limitations for the diagnosis of clinical samples and prognostic assessment. Through the integration of multi-omics research methods and experimental validation, the mechanisms underlying lactylation will become clearer in the future. This review summarizes the role of lactylation in the onset, progression, and treatment resistance of gastrointestinal tumors and non-malignant liver diseases, as well as its associated limitations and future prospects. It provides guidance for developing precision medicine strategies targeting lactylation modifications to improve clinical outcomes for patients with complex diseases. This research was supported by the Liaoning Provincial Science and Technology Program Joint Project (Grant Number: 2023JH2/101700082).