Lactate and lactylation in liver diseases: energy metabolism, inflammatory immunity and tumor microenvironment

Abstract

Liver diseases pose a significant threat to human health. Lactate, a byproduct of glycolysis, serves various biological functions, including acting as an energy source, a signaling molecule, and a substrate for lactylation. Lactylation is a novel lactate-dependent post-translational modification that plays a role in tumor proliferation, the regulation of immune cell function, and the modulation of gene expression. In this paper, we summarize the roles of lactate and lactylation in energy metabolism, inflammatory immunity, and the tumor microenvironment, while also elucidating recent research advancements regarding lactate and lactylation in the context of hepatic fibrosis, non-alcoholic fatty liver disease, and hepatocellular carcinoma. Furthermore, lactate and lactylation are proposed as promising new targets for the treatment of liver diseases.

Keywords: immunology; lactate; lactylation; liver diseases; metabolism.

Figure 1

Lactate plays a crucial role in regulating immune cells within the TME. Through metabolic reprogramming, tumor cells release lactate, creating an acidic milieu. This lactate aids tumors in evading immune surveillance and stimulates their growth by modulating the functionality of immune cells. Specifically, lactate drives the polarization of TAMs (tumor-associated macrophages) toward the M2 phenotype, promoting anti-inflammatory actions that enhance tumor progression. Moreover, lactate alters the functions of T cells, Tregs, NK cells, and dendritic cells, enabling immune evasion. The lactate-mediated immunosuppressive network thereby supports tumor growth and infiltration.

Figure 2

The production of lactate and its role in liver diseases. Glucose is converted to pyruvate, with glucose-6-phosphate (G-6-P) and phosphoenolpyruvate (PEP) as intermediate products. Pyruvate is reduced to lactate or enters the tricarboxylic acid (TCA) cycle. In NAFLD, lactate enhances SREBP1 activity and promotes lipid accumulation by inhibiting AMPK. In addition, GPR81 deletion exacerbates hepatic lipid accumulation. In acute liver injury, lactate inhibits TLRs through GPR81, thereby inhibiting NLRP3 activation and reducing the inflammatory response. In liver fibrosis, lactate and glycolytic enzymes increase glycolysis levels in HSCs, worsening liver fibrosis. In HCC, upregulation of MCTs and LDHA accelerates HCC progression by elevating lactate levels.

Figure 3

The mechanism of lactylation and its role in liver diseases. Lactate derived from glucose is converted into Lactyl-CoA, and the lactate group is added to the proteins under the action of “Writer”. In liver fibrosis, lactylation is involved in the transformation of quiescent hepatic stellate cells (qHSCs) into activated hepatic stellate cells (aHSCs). In HCC, lactylation enhances the proliferation and invasion of cancer cells. In NAFLD, lactylation mainly reduces lipid accumulation. In AILI, NEDD4 lactylation promotes non-canonical pyroptosis pathways and exacerbates liver injury.