Histones are basic DNA-binding proteins found in chromosomes. The nucleosome, the fundamental repeating unit of chromatin, consists of 146 bp DNA wrapped around an octamer of the core histones (H2A, H2B, H3, and H4), along with the linker histone H1 (Nitsch et al., 2021). Histone lactylation primarily occurs on lysine residues. It modifies chromatin structure and function by altering the net charge of histones and influencing the binding affinity between histones and DNA. This leads to chromatin relaxation and easier recognition and binding of transcription factors, thereby activating gene expression (Luger et al., 2012).

Lactylation on the same site may exert diverse pathophysiological effects through downstream signaling on anti-inflammation, angiogenesis, and tumor proliferation and invasion. H3K18la can not only increase the level of YTH N6-Methyladenosine RNA Binding Protein F2, the reader of methylation to drive ocular melanomagenesis (Yu et al., 2021), but also activate the transcription of platelet-derived growth factor receptorβ in von Hippel-Lindau-mutated clear cell renal cell carcinomas which in turn increases lactylation levels and forms an oncogenic positive feedback loop (Yang J. et al., 2022). Moreover, H3K18la is also linked to the severity of septic shock (Chu et al., 2021) and SA-AKI (Qiao et al., 2024), the promotion of embryo implantation and its growth (Li J. et al., 2024), and the macrophage phenotype switch from M1 to M2 (Zhang et al., 2019). Apart from H3K18la, more and more histone lactylation sites are found to be involved in diverse diseases. For example, glycolysis aggravates microglia dysfunction in Alzheimer’s disease through the H4K12la/PKM2 positive feedback loop (Pan R. Y. et al., 2022). Triterpenoid antitumor compound demethylzeylasteral suppresses the proliferation of hepatocellular carcinoma (HCC) stem cells and impedes HCC progression by reducing H3K9la and H3K56la (Pan L. et al., 2022).

Non-histone lactylation mainly occurs on lysine residues as well. It regulates protein function by affecting steric hindrance, conformational changes, and charge neutralization (Yang et al., 2024). For example, it alters molecular interactions, enzyme activity, and subcellular localization of the proteins.

So far, the majority of the research conducted on lactylation has focused on histone lactylation instead of non-histone lactylation. Nonetheless, several studies have demonstrated the importance of non-histone lactylation in regulating gene transcription and signal transduction. Luo et al. found that (Luo et al., 2022) lactate imported to cells by MCT1 helps to stabilize hypoxia inducible factor-1α (HIF-1α) via its lactylation which enhances the transcription of cell migration-inducing protein to promote angiogenesis and vasculogenic mimicry in prostate cancer. After cerebral infarction, lactate accumulates in ischemic and hypoxic tissues and induces lymphocyte cytosolic protein 1 (LCP1) lactylation, which can stabilize LCP1, thus aggravating neuron injuries and the progression of cerebral infarction (Zhang W. et al., 2023).

There are 2 enantiomers of lactate in the human body, L-lactate and D-lactate, the former of which is predominant. Meanwhile, there are two pathways of lactylation: L-lactylation and D-lactylation (Xu B. et al., 2024), also known as direct lactylation and indirect lactylation (Figure 1). L-lactylation is an enzymatic reaction which is mostly catalysed by non-specific acetyltransferases utilizing lactoyl CoA as the donor of lactyl group; recently it has been found that alanyl-tRNA synthetases 1 (AARS1), a specific lactyltransferase, binds to lactate and catalyzes the formation of lactate-AMP, followed by transfer of lactate to the lysine residue (Zong et al., 2024). On the other hand, D-lactylation, also referred to as non-enzymatic lactylation, utilizes S-D-lactoylglutathione (LGSH) as the donor of lactyl group and indirectly delivers lactyl group through a non-enzymatic process (Gaffney et al., 2020). L-lactylation is the predominant pathway in cells (Zhang D. et al., 2024), which is also the main pathway influenced by glycolysis since it dynamically regulates lactyl CoA.

The process of lactylation is influenced by lactate metabolism and transport, acetyltransferases, deacetylases, and regulatory proteins. Lactate and lactylation levels are decreased when glycolysis inhibitors are used but increased when inhibitors of mitochondrial electron-transport-chain are used (Qiao et al., 2024). In addition, gene expression can in turn affect lactylation and form a positive/negative feedback loop of epigenome-metabolome-epigenome. Other factors that may influence lactylation include neuronal excitability (Hagihara et al., 2021), crosstalk with other PTMs and so on. Non-enzymatic lactylation is regulated by LGSH and glyoxalase 2 (Gaffney et al., 2020). The regulatory functions of enzymes in enzymatic lactylation are primarily summarized below.

There are 3 types of lactylation-related enzymes: writers are transferases to add the lactyl group, erasers are deacetylases to remove the lactyl group, both of which dynamically regulate lactylation; the reader is a binding protein to recognize lactylation and deliver transcriptional signals (Gao et al., 2024).

Histone acetyltransferase (HAT) family functions as the writer, among which research has demonstrated that p300 and CREB-binding protein (CBP) (Yang K. et al., 2022) participate in the catalytic process of lysine lactylation, thus activating high mobility group protein box1 (HMGB1) gene expression. In contrast, inhibition of p300/CBP significantly lowers the expression of HMGB1 in macrophage cytoplasm. HDAC acts as an eraser to remove lactyl group, which can be categorized into two types. The first type includes class I, II, and IV HDAC consisting of HDAC1-11 (Xu et al., 2021), among which HDAC1-3 have the strongest activity of both de-L-lactylation and de-D-lactylation (Moreno-Yruela et al., 2022); The other type includes class III HDAC consisting of sirtuin 1–7 (SIRT), among which SIRT1-3 have strong activity of de-L-lactylation. It has been discovered (Jin et al., 2023) that SIRT3 prevents HCC from spreading by promoting the delactylation of non-histone cell cycle protein E2. Different from the non-specific enzymes mentioned above, AARS1 and AARS2 are specific lactyltransferases and sensors for lactate. They have been recently reported to promote the lactylation of p53 (Zong et al., 2024), Yes-associated proteins (Ju et al., 2024), and cyclic GMP-AMP synthetase (Li et al., 2024a), thus participating in the proliferation and immune escape of tumor cells. Meanwhile, β-alanine can bind to AARS1 competitively due to its structural similarity with lactate, reverse the process of lactylation and enhance the effect of cancer chemotherapy. Fewer studies have been done on the reader of lactylation. Hu et al. found for the first time that Brahma-related gene 1(BRG1) functions as a reader for H3K18la and participates in mesenchymal-epithelial transition (Hu et al., 2024). The summary of enzymes involved in lactylation and part of their substrate were listed in Table 2.

Lactylation-related enzymes are important regulators of lactylation. Therapeutic strategies for associated diseases can be further explored by altering enzyme activity to control lactylation levels and directly regulate downstream signaling. However, the study of enzymes in lactylation is still in its early stage and more regulatory proteins need to be identified, especially the reader. In addition, given that several different PTMs share the same enzymes, whether there is any competition among them and what the specific mechanism is still need to be further explored.

AKI is a clinical syndrome characterized by a sudden impairment of kidney function which poses a serious threat to the patient’s life. It typically occurs during infection, trauma, and surgery, tending to be caused by various injuries such as kidney hypoperfusion, sepsis, major surgery, immune diseases, and the use of radiocontrast or nephrotoxic drugs. Poor regeneration (Hoste et al., 2018) following AKI also results in continuous deterioration in kidney function and exacerbation of kidney fibrosis, which is a risk factor for CKD and ESKD.

IRI is the primary cause of AKI (Xin et al., 2022), leading to abnormal apoptosis and inflammatory responses in renal tubular cells which is the key pathological mechanism of AKI. The low perfusion during IRI results in hypoxia, high glycolysis activity, and the accumulation of lactate and pyruvate in proximal tubular epithelial cells (PTCs). High level of lactate is an independent risk factor for the severity of SA-AKI (An et al., 2023). AST-120 (Kremezin), an oral spherical carbon adsorbent approved for CKD treatment, has been demonstrated that oral administration of it helps to alleviate IRI (Shen et al., 2021) and mitigate AKI progression. To explore whether it is related to histone lactylation, Zhou et al. established an IRI mouse model and found that the level of HK2, the key enzyme of glycolysis, increased in IRI mice while the knockout of the Hk2 results in decreased biomarkers of PTC injury and cell death compared to the wild type (Zhou J. et al., 2024). In the presence of Hk2, AST-120 exerts the protective effect described above on the kidney through inhibiting glycolysis in PTC. Further mechanistic study revealed that it might be on the ground that HK2 promoted glycolysis and the production of lactate, thus inducing a significant increase in the pan-lactylation levels as well as the histone lactylation levels, especially H3K18la. Moreover, H3K18la is enriched at the promoter of Hk2 and activates its overexpression which then promotes glycolysis in turn and forms a positive feedback loop of H3K18la-HK2-glycolysis. The loop consequently exacerbates IRI and accelerates AKI progression.

SA-AKI is usually characterized by sepsis or septic shock which is an organ dysfunction syndrome resulting from a dysregulated host response to infection and leads to progressive deterioration of kidney function (Poston and Koyner, 2019). It is strongly associated with poor clinical outcomes compared to non-septic AKI. Serum lactate is considered a prognostic biomarker of sepsis. TECs are one of the most metabolically active cells in the kidney, sensitive to sepsis-associated injury. EZR is a gene that encodes a protein named Ezrin, which belongs to the ezrin-radixin-moesin family. It is a crucial actin-binding protein that links membranes to actin filaments during lamellipodia formation, cell polarization, migration and signal transduction (Yin and Schnoor, 2022). Pan et al. found that H3K18la and ezrin K263la levels are increased as lactate accumulates in the cecal ligation and puncture mice and in LPS-treated PTCs (Pan R. Y. et al., 2022). Mechanistic studies have shown that H3K18la is enriched at the promoter of the Ras homolog gene family member A (RhoA) and increases its transcriptional activity, which aggravates inflammatory response, oxidative stress, and cell apoptosis in PTCs through the RhoA/Rho-associated kinase/Ezrin signaling axis. Moreover, increased levels of Ezrin K263la activate the Nuclear Factor kappa B (NF-κB) signaling pathway while Ezrin K263R (lysine at position 263 mutated to arginine, K for lysine) attenuates PTC injury. This study establishes a link between lactylation and SA-AKI, which may be a potential therapeutic target for regulating epigenetic modifications and metabolism in PTCs. An et al. found synergetic effects from acetylation and lactylation of non-histone in SA-AKI, providing a new idea about the role of crosstalks between multiple PTMs in kidney diseases (An et al., 2023). They found that decreased SIRT3 level in sepsis mice is accompanied by the hyperacetylation and inactivation of PDH E1 component subunit alpha (PDHA1), which leads to excessive lactate production in TECs and promotes mitochondrial fission 1 (FIS1) K20la. Mitochondria in living cells exist as a dynamic network that continuously cycle through fusion and fission events (Fenton et al., 2021). Mitochondrial fission is mainly controlled by FIS1 and the dynamin related protein 1 (DRP1), both of which exacerbates mitochondrial hyperfission, ATP depletion, reactive oxygen species (ROS) overproduction, and cell apoptosis (Egner et al., 2022). In contrast, treatment with PDHA1 activators or LDH inhibitors which increased SIRT3 levels could reverse the exacerbation of SA-AKI. Therefore, decreasing lactate production and FIS1 lactylation may be a new potential treatment to amoeliorate TEC injury and alleviate SA-AKI.

In addition, it has been found (Kim et al., 2020) that allicinol mitigates the oxidative stress, inflammatory response, and cell apoptosis in AKI induced by cisplatin at least partly through inhibiting p300-mediated epigenetic mechanisms which decreases lactylation levels of histone 3, non-histone p53 and NF-κB p65; and Tang et al. found that class I HDAC played an important role in promoting TEC protection and regeneration (Tang et al., 2014). As shared enzymes of both acetylation and lactylation, the role p300 and HDAC play in the course above may link to lactylation as well, which deserves to be further explored from the perspective of PTMs crosstalks.

The global prevalence of CKD has exceeded 10% which is a serious public health problem and needs to be solved urgently (Kovesdy, 2022). CKD is a long-term and slow-progressing disease, usually caused by other chronic diseases such as hypertension, diabetes mellitus, systemic lupus erythematosus, chronic nephritis, kidney stones, and gradually progressing AKI or usage of nephrotoxic drugs. With the fast-growing aging population and a significant increase in the prevalence of diabetes mellitus and hypertension, the incidence of CKD has been rising annually. Therefore, it is crucial to push forward early detection, management, and treatment of CKD to slow down the progression of the disease and protect kidney function at an early age.

Renal fibrosis is a common pathological feature of CKD and is characterized by renal tubular atrophy, chronic inflammation of the interstitium, myofibroblast activation, and ECM deposition (Huang et al., 2023). A significant accumulation of lactate and metabolic reprogramming of glycolysis has been observed in PTCs of CKD patients and animal models (Eymael et al., 2023), and pharmacologically suppressing glycolysis helps to prevent kidney fibrosis (Ding et al., 2017). This suggests a close correlation between lactate accumulation and progressive fibrosis in the kidney.

To further reveal the role lactylation plays in kidney fibrosis, Wang et al. explored the specific effect of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase3 (PFKFB3) on kidney fibrosis, which is a key enzyme of glycolysis (Wang Y. et al., 2024). Researchers found that PFKFB3 level significantly increases in the kidney tissues of CKD patients. Mainly localized in PTCs, it negatively correlates with kidney function while positively correlates with the degree of kidney fibrosis and levels of lactylation. Combining in vitro experiments for mechanistic studies, they found that PFKFB3 induces lactate accumulation and histone lactylation, especially H4K12la, through mediating metabolic reprogramming of glycolysis in PTCs. Furthermore, H4K12la is enriched at the promoter of the NF-κB pathway-related genes such as IκB kinaseβ (Iκbkb), Rela, and Relb, and activates target gene transcription and NF-κB signaling pathway which results in aggravating kidney inflammatory response and fibrosis. In addition, knockout of Pfkfb3 or treatment with 3PO, which is a small-molecule inhibitor of PFKFB3 can decrease levels of H4K12la and significantly suppresses the activation of NF-κB signaling pathway, remarkably attenuating kidney interstitial fibrosis and collagen deposition in IRI mice. Furthermore, recent research has demonstrated that PFKFB3 inhibitors, such as 3PO, showed a great prospect of targeting cancer cells (Kotowski et al., 2020) which is also expected to be a potential treatment for kidney fibrosis.

CKD patients are prone to develop vascular calcification due to internal imbalance of calcium and phosphorus metabolism, increased oxidative stress, and loss of calcification inhibitors (Cannata-Andía et al., 2021). Medial artery calcification (MAC) is a systematic chronic vascular disease that is common in the elderly, CKD, and diabetic patients. Different from the intimal damage in atherosclerosis, osteogenic transdifferentiation takes place in a pro-calcific CKD milieu in vascular smooth muscle cells (VSMCs) and matrix vesicles are secreted to provide a microenvironment for calcified crystals deposition, which is a key event for MAC onset and progression (Wang Z. et al., 2024). MAC is a highly risky factor for high cardiovascular morbidity and mortality in CKD patients. Ma et al. found that the level of nuclear receptor subfamily 4 group A member 3 (NR4A3) increases in CKD mice calcified aortic tissues (Ma W. et al., 2024), and the deficiency of it reduces the glycolysis and histone lactylation during calcification. Further mechanistic studies suggested that NR4A3 promotes lactate production by directly binding to the promoter of Aldolase A and Phosphofructokinase, liver type, and activating their transcription, which then increases H3K18la levels. Enriched at the promoter of Phosphoethanolamine/Phosphocholine Phosphatase 1, H3K18la activates its transcription which releases inorganic phosphorus doped into the mineral phase by hydrolyzing its substrates, thus promoting arterial calcification in CKD. Given that histone lactylation is reversible and has a close relation with kidney fibrosis and inflammation, decreasing its levels is expected to be a new target for the prevention and treatment of CKD and its complications.

Diabetic kidney disease (DKD) is a chronic kidney disease caused by diabetes mellitus, which is the most common microvascular complication of diabetes and can develop into ESKD (Zhang X. et al., 2024) as well. Chronic hyperglycemia brings several complex pathophysiological changes within kidney tissues, such as foot process diffuse effacement, glomerular basement membrane thickening, mesangial matrix proliferation, and glomerulosclerosis. These changes ultimately result in proteinuria, hypertension, tubular injury, decreased glomerular filtration rate, and progressive renal failure (Reidy et al., 2014). The progression of DKD is largely influenced by kidney metabolic dysregulation, mitochondrial dysfunction, and increased glycolysis, which result in greater lactate production (Lee et al., 2022). Chen et al. further explored the role metabolic reprogramming played in DKD (Chen et al., 2024). They found high levels of lysine lactylation in DKD patients and mice kidneys, most of which occur in mitochondria. DKD progression is aided by the lactylation of acyl-CoA synthetase family member 2 K182 in PTC mitochondria which further aggravates ROS hyperaccumulation and mitochondrial dysfunction.

A major factor contributing to DKD is commonly acknowledged to be the epithelial-mesenchymal transition (EMT), which is characterized by the acquisition of a mesenchymal phenotype and the loss of the epithelial cell polarity and intercellular adhesion. Zhang et al. found that glycolytic gene expression is upregulated in DKD patients and mice kidneys, accompanied by mitochondrial dysfunction and elevated lactate levels, which consequently decreases the expression of epithelial cell markers and increases the expression of mesenchymal cell markers (Zhang X. et al., 2024). Further study in mechanisms revealed that as a precursor, lactate significantly increases the pan-lactylation levels as well as H3K14la levels in TECs, which is enriched at the promoter of Krüppel-like factor 5 (Klf5) and facilitates its transcription. Excess KLF5 binds to the promoter of Cadherins 1 and inhibits its expression, thus promoting the progression of EMT (Li et al., 2021). Nephro-specific knockdown or pharmacological inhibition of KLF5 can alleviate EMT which is a potential strategy for DKD therapy.