Lactate and lactylation: emerging roles in autoimmune diseases and metabolic reprogramming

Abstract

Autoimmune diseases are a set of conditions in which the immune system incorrectly identifies and attacks the body's own healthy tissue, severely compromising patient health. While current treatments can somewhat control disease progression, their long-term effectiveness remains limited, necessitating the development of more effective therapeutic approaches. Lactate and lactylation are critical links between metabolic reprogramming and epigenetics. As an emerging epigenetic modification, lactylation induced by lactate is closely associated with the onset of autoimmune diseases. Lactylation can be categorized into histone and nonhistone modifications, both of which play pivotal roles in cellular functions and pathophysiological processes through distinct regulatory mechanisms. Lactylation impacts immune cell function by regulating metabolic reprogramming and signaling pathways. In autoimmune diseases, immune cell metabolic reprogramming controls lactylation levels through metabolic byproducts, and lactylation, in turn, modulates the cellular metabolism by altering the transcription and structure of key enzymes. These interconnected processes collectively drive disease progression. To better understand the role of lactate and lactylation in the pathogenesis of autoimmune diseases, this review synthesizes the effects on specific immune cells, examining their dual effects on immune system function and their particular impacts on two common autoimmune diseases-rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). By combining the established role of lactate in immune metabolic reprogramming with the emerging understanding of the influence of lactate-induced lactylation on epigenetic regulation, this paper explores the relationship between lactylation and the progression of autoimmune diseases. This approach aims to enhance the understanding of the interplay between epigenetics and metabolism in autoimmune disease development, providing new perspectives for future therapeutic strategies. Studies collectively indicate that treatment can be improved through regulating key enzymes involved in lactylation, targeting lactate production pathways, integrating innovative approaches with current therapies, and adopting personalized treatment strategies.

Keywords: autoimmune diseases; epigenetics; lactate; lactylation; metabolic reprogramming.

Figure 1

The process of lactylation. After lactate molecules enter the cell, they are converted into lactyl-CoA by CoA transferase. Lactyl-CoA then moves from the cytoplasm into the nucleus, where it is recognized and bound by the “writers.” The “writers” subsequently transfer the lactyl group onto histones. Histones that have undergone lactylation can then be recognized by the “readers,” which mediate their functional effects. The lactylation process is reversible, with “erasers” removing the lactyl group, thereby resulting in de-lactylation. MCT, monocarboxylate transporter; Kla, lysine lactylation; ALCT, CoA transferase.

Figure 2

Aerobic glycolysis in immune cells. Glucose enters the cell and is phosphorylated by HK to form Glucose-6-P. The pentose phosphate pathway (PPP) operates alongside glycolysis, where Glucose-6-P serves as a substrate, generating NADPH, which is subsequently converted into R5P. R5P is essential for nucleotide synthesis, while NADPH serves as a reducing agent in biosynthesis and protects the cell from oxidative stress. In glycolysis, Glucose-6-P is converted into Fructose-6-P. PFKFB3 catalyzes the conversion of Fructose-6-P into Fructose-2,6-BP, which enhances PFK1 activity, promoting the conversion of Fructose-6-P to Fructose-1,6-BP. Fructose-1,6-BP undergoes several reactions to form phosphoenolpyruvate, which is then converted to pyruvate by PKM2. During aerobic glycolysis, 5% of pyruvate is converted to Acetyl-CoA, while 85% is converted to lactate by LDH. The generated lactate partly enters the nucleus, with the remainder transported outside the cell. GLUT, Glucose transporter; HK, Hexokinase; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; PFK1, Phosphofructokinase 1; PKM2, Pyruvate kinase M2 isoform; LDH, Lactate dehydrogenase; MCT, Monocarboxylate transporter; Acetyl-CoA, Acetyl-CoA; TCA cycle, Tricarboxylic acid cycle; OXPHOS, Oxidative phosphorylation.

Figure 3

Metabolic reprogramming of immune cells in the context of rheumatoid arthritis and systemic lupus erythematosus. DC, dendritic cell; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TCA, tricarboxylic acid cycle.

Figure 4

Lactylation enhances IFN-I production by blocking the ubiquitination and degradation of cGAS. In the normal ubiquitin-proteasome system, the Ub molecule is activated by E1 through ATP hydrolysis and then transferred to E2. The E2-Ub complex marks cGAS for degradation via MARCHF5, an E3 ubiquitin ligase. In patients with SLE, mtDNA stimulation enhances cellular glycolysis, resulting in increased lactate production. The accumulation of lactate leads to the lactylation of cGAS, which blocks its ubiquitination. The undisturbed cGAS activates downstream STING signaling, which in turn activates TBK1. TBK1 then phosphorylates IRF3, which translocates to the nucleus to promote DNA transcription and production of IFN-I, thereby enhancing the immune response. Ub, ubiquitin; E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; MARCHF5, an E3 ubiquitin ligase; cGAS, cyclic GMP-AMP synthase; mtDNA, mitochondrial DNA; Kla, histone lysine lactylation; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1; IRF3, interferon regulatory factor 3; IFN-I, type I interferon.