Abstract
Lactylation, a recently identified post-translational modification, was initially characterized as lysine residue modification in histone subunits that regulates gene transcription via epigenetic mechanisms. Elevated intracellular lactate has been shown to drive histone lysine lactylation (Kla), establishing its association with disease pathogenesis. Emerging evidence reveals that Kla modifications extend beyond histones to transcriptional regulators and cytoplasmic functional proteins. Unlike the broad transcriptional regulation mediated by histone lactylation, Kla modifications of functional proteins exert regulatory effects through both specific transcriptional modulation and direct functional alteration of target proteins, thereby precisely controlling biological processes. This review systematically examines the pathological implications of Kla modifications of functional proteins across multiple disease contexts, including inflammatory disorders, infectious diseases, neurological or cardiovascular pathologies, and oncological conditions. Our synthesis provides mechanistic insights into disease-associated Kla networks, facilitating therapeutic target discovery and pharmacological intervention strategies.
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Facts
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Kla modifications on non-histone proteins, such as transcription factors and enzymes, exhibit regulatory effects on gene transcription and protein function, but the precise mechanisms distinguishing pathological from physiological Kla modifications remain unclear, warranting further investigation into context-specific writers and erasers.
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While elevated lactate-driven Kla modifications have been linked to disease progression in inflammation, infections, neurological disorders, cardiovascular pathologies and cancers, the therapeutic potential of targeting specific Kla-modified proteins for pharmacological intervention is underexplored and could reveal novel druggable pathways.
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The crosstalk between Kla modifications and other PTMs on functional proteins may amplify or antagonize disease phenotypes, posing a key debatable area for future studies on integrated PTM networks in pathological conditions.
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Emerging evidence suggests Kla modifications extend to cytoplasmic and organellar proteins beyond the nucleus, but their roles in metabolic reprogramming and cellular homeostasis during disease states require further mechanistic elucidation to guide precision medicine approaches.
Introduction
Enhanced glycolytic flux, a hallmark of diverse pathological states including inflammation, organ injury, viral infections, neurological damage, cardiovascular disorders, and malignancies, drives lactate dehydrogenase A (LDHA) upregulation and consequent lactate overproduction [1,2,3,4,5,6]. In 2019, pioneering work from the University of Chicago employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify lysine lactylation (Kla) sites on histone H3 across human and murine cells [7]. This breakthrough revealed that Kla modification on K18 of histone H3 (H3K18la) functions as a transcriptional activator. These findings established Kla as a pivotal player in post-translational regulation, sparking intense research interest in its epigenetic roles.
The eukaryotic nucleosome core comprises an octamer of histone subunits (H2A, H2B, H3, H4) that organizes genomic DNA [8, 9]. Dynamic post-translational modifications (PTMs) such as methylation and acetylation at specific histone residues modulate histone-DNA interactions, thereby regulating chromatin compaction states and transcriptional accessibility [10,11,12,13]. Emerging evidence now extends this paradigm to lactylation, with the Kla-modified sites identified on H3, H4, and H2B subunits, though H2A remains conspicuously devoid of detectable Kla modification [14,15,16]. Among Kla-modified histones, histone H3 exhibits the highest lactylation density and functional significance, particularly at the H3K18 site [17,18,19].
Elevated H3K18la levels can activate inflammation-related pathways, thereby promoting oxidative stress and apoptosis, which ultimately lead to renal dysfunction [20]. Similarly, in multiple cancers, increased H3K18la levels can regulate the transcription of genes associated with tumor growth and metastasis, thereby facilitating tumorigenesis and progression [19, 21, 22]. Besides, intracellular lactate stress can also activate Kla modifications of histone H3 at K9, K14, and K56 to remodel chromatin structure and facilitate gene transcription, further promoting inflammation and cancer progression [17, 23,24,25].
Kla modifications on histone H4 have also been shown to play significant roles in regulating gene transcription. Specifically, the H4K12la modification is considered to be critical in the onset and development of neurological, oncological, and cardiovascular diseases [15, 26,27,28]. H4K12la can activate the expression of inflammation and glycolysis-related proteins, thereby promoting the progression of Alzheimer’s disease through the activation of microglial autophagy-related signaling pathways and glycolysis [26, 27]. Moreover, H4K12la can also facilitate the progression of atherosclerosis and tumors by activating the transcription of genes associated with aging and metabolism [15, 28]. Additionally, H4K5la and H4K8la have also been reported to promote disease progression [29,30,31].
In contrast, modifications of histone H2B have been less frequently reported. In hepatocellular carcinoma (HCC), histone H2B can be Kla-modified at K58, thus facilitating the transcription of NDRG1 to inhibit cell senescence and apoptosis [16]. Moreover, H2BK16la modification has been identified in cells infected by classical swine fever virus (CSFV), which mediates the nuclear translocation of p65 via karyopherin α2 (KPNA2), thereby inducing the expression of interferon-λ (IFN-λ) to counteract viral infections [32].
Overall, Kla modifications on histone subunits exhibit extensive regulatory functions in gene transcription, playing a pivotal role in both the pathogenesis of diseases and the maintenance of normal physiological functions.
Some studies have used immunofluorescence staining to detect total cellular Kla modification, and it is clear that Kla-modified proteins are predominantly distributed in the nucleus, although signals are also present in the cytoplasm and some organelles [33, 34]. Immunoblotting analysis of whole cell lysates has revealed that although histone H3 and H4 show the strongest signals of Kla modification, other proteins also exhibit Kla modifications [35, 36]. These studies indicate that Kla modification occurs not only on histones but also on other functional proteins, thus regulating cellular physiological and biochemical functions.
The following studies have shown that Kla modification is present on transcription factors (TFs), enzymes, secretory proteins, and cellular signaling-related proteins [20, 37,38,39]. Kla modification regulates the activation and nuclear translocation of TFs, protein secretion, the interactions between signaling-related proteins and their downstream proteins, the activity of enzymes, including metabolic enzymes, E3 ubiquitin ligases, and mRNA modification-related enzymes [20, 39,40,41,42,43]. Additionally, some studies have also demonstrated that Kla modification not only impacts the function of proteins but also regulates protein stability, thereby upregulating specific proteins and influencing downstream physiological and biochemical functions [44, 45].
In this review, we have summarized the recent studies on Kla modifications of functional proteins according to the research fields, in order to provide direction for future studies on Kla modification.
The Kla modifications of functional proteins in inflammation
Inflammation is an immune response produced by the body to damaged tissues and external stimuli [46]. It is a defense mechanism aimed at isolating and eliminating the source of tissue damage, as well as repairing the tissues [47, 48]. In inflammatory tissues, local macrophages, dendritic cells, and T lymphocytes are activated to release various cytokines and chemicals such as interleukins (ILs), tumor necrosis factors (TNFs), granzyme B, and histamine [49,50,51]. These molecules exert functional roles in killing pathogen-infected or necrotic cells, promoting vasodilation and increasing vascular permeability [52,53,54]. However, if the stimulus is not promptly removed and continues to affect these cells, it may lead to excessive secretion of these cytokines and chemicals [55]. This process can activate pro-inflammatory cytokines, such as IL-1β and IL-18, exacerbating tissue inflammation, leading to cellular damage, and ultimately resulting in inflammatory diseases [56, 57]. Many studies have confirmed that inflammation promotes glycolysis, leading to enhanced LDHA activity and lactate accumulation in the microenvironment [58,59,60,61]. Therefore, the studies of Kla modifications of functional proteins in inflammatory diseases are actively underway. Herein, we will discuss the specific roles of Kla modifications in modulating inflammatory responses (Fig. 1).
The metabolic reprogramming of immune cells leads to elevated lactate levels within cells during acute and chronic inflammation, leading the Kla modifications of functional proteins to facilitate or inhibit the process of inflammation. The Kla modifications of Acly-L, YY1, TWIST1, Ezrin, RelA and EGR1 facilitate or inhibit the transactivation of pro-inflammatory cytokines to aggravate or relieve inflammation. Besides, the Kla-modified ALDH2 and NEDD4 could also facilitate inflammation via inducing cell apoptosis or pyroptosis. The Kla-modified FAS can reduce the level of MPC1, resulting in accumulation of intracellular lactate to facilitate the process of glycolysis. Moreover, the Kla-modified HMGB1 can be secreted into the extracellular spaces to activate the chemotaxis of macrophages, causing cell damage.
Cytokine storm, primarily caused by the transcriptional activation of pro-inflammatory cytokines, is considered as the dominant factor contributing to inflammatory diseases [62, 63]. The excessively released pro-inflammatory cytokines can cause vascular damage and organ failure through activating cell death [64, 65]. Some studies have indicated that Kla modifications promote the nuclear translocation of EGR1 and TWIST1, thus activating the transcription of genes encoding heparinase or pro-inflammatory cytokines, resulting in lung injury and skin fibrosis [37, 66]. In addition to promoting the nuclear entry of TFs, Kla modification can also regulate the activity of the TFs themselves, thereby modulating the transcriptional activation of pro-inflammatory cytokines. In autoimmune uveitis, the elevated lactate levels in microglia can lead to the Kla modification of Yin Yang 1 (YY1), thereby promoting the transcriptional activation of genes such as signal transducer and activator of transcription 3 (STAT3), chemokine (C-C motif) ligand 5 (CCL5), indoleamine 2,3-dioxygenase 1 (IDO1), and semaphorin 4 A (SEMA4A), which in turn promotes the development of inflammation [67].
The high lactate environment, in addition to regulating TFs through Kla modifications, can also promote the development of inflammatory diseases by modulating enzymatic activities. In acute kidney injury, ALDH2 is Kla modified at K52, which exacerbates tubular damage and mitochondrial dysfunction via attenuating its interaction with prohibitin 2 (PHB2), thus facilitating the ubiquitin-proteasome-dependent degradation of PHB2 [38]. However, the Kla modification of specific proteins also bring positive responses. In some cases, it is discovered that delactylation of some enzymes can also aggravate disease progression. For instance, during the activation of inflammatory macrophages, L-ATP citrate lyase (Acly-L) undergoes Kla modification, which inhibits its enzymatic activity, thereby restricting the productions of IL-1β and IL-6 and attenuating inflammation. In contrast, Acly-S, another isoform of ATP citrate lyase, can not be Kla modified, which leads the expression of excessive IL-1β and IL-6, contributing to rheumatoid arthritis [68]. Another study found that lactylation of fatty acid synthase (FAS) at K673 inhibits its enzymatic activity, reducing fatty acid synthesis, which impairs mitochondrial function and suppresses MPC1 expression through metabolic stress signals (e.g., ROS or AMP/ATP ratio), ultimately alleviating non-alcoholic fatty liver disease symptoms [41]. Kla modifications not only regulate metabolic enzymes but also modulate the activity of E3 ubiquitin ligases. Acetaminophen can induce Kla modification of NEDD4, an E3 ubiquitin ligase, in liver cells, inhibiting its ubiquitination of caspase-11, thereby activating pyroptosis to promote liver injury [42].
Signal transduction-related proteins, mitochondrial-resident proteins, and secretory proteins can also be Kla modified to mediate organ damage. In sepsis, the Kla modification of the signal transduction protein Ezrin induces the activation of nuclear factor κ-B (NF-κB) pathway, thus promoting inflammation to induce cell apoptosis and kidney damage [20]. Besides, the Kla modification of mitochondrial fission 1 protein (Fis1) promotes excessive mitochondrial fission, depleting ATP and generating excessive reactive oxygen species (ROS) to induce apoptosis and kidney damage [69]. Furthermore, in liver injury models, the Kla modification of high mobility group box-1 protein (HMGB1) promotes its secretion, leading to macrophage chemotaxis and causing liver damage [39].
In addition to the common L-lactylation, a fraction of proteins can also undergo D-lactylation modification. Under normal metabolic conditions, RelA can be D-lactylated, which suppresses its transcriptional activity, leading to reduction of pro-inflammatory cytokines, preventing excessive immune cell activation and pathological damage caused by inflammation, and restoring immune homeostasis [70]. Therefore, Kla modification may not always promote inflammation but could also have an inhibitory effect.
The aforementioned studies demonstrate that the Kla modifications of functional proteins play crucial roles in the occurrence and development of inflammation. It can exacerbate inflammation and cause organ damage by activating the transcription of pro-inflammatory cytokines and promoting the generation of pro-apoptotic factors, or suppress inflammation by inhibiting the activity of inflammation-related TFs, thus maintaining immune homeostasis.
The Kla modifications of functional proteins in infectious diseases
When host cells are infected by pathogens, pattern recognition receptors (PRRs) will be activated, leading to the production of pro-inflammatory cytokines (e.g., Il-1β, TNF-α and IL-6) through the activation of the NF-κB and interferon regulatory factor 3 (IRF3) signaling pathways and enhancing the Warburg effect in macrophages and T cells [71,72,73,74]. Additionally, pathogens-originated toxins, such as Staphylococcus Aureus α-toxin, can facilitate the formation of plasma membrane pores, leading intracellular ATP depletion and activating the AMPK pathway, thereby initiating glycolysis [75, 76]. Both the pathways above contribute to intracellular lactate production and promote protein Kla modification. Kla modifications of pathogen proteins and host intracellular functional proteins can both promote pathogen replication, thereby facilitating infection and activating inflammation-related signaling pathways to counteract infection. The Kla modifications of pathogen and host intracellular functional proteins play a dual role in infectious diseases (Fig. 2). The roles of the proteins will be introduced in detail in the following sections.
Elevated lactate levels are observed in the microenvironment of some infectious diseases. In tissues with high lactate content, cGAS can be Kla-modified, leading its dysfunction to recognize dsDNA and the production of anti-infective cytokines. Besides, the Kla modification of RUBCN can promote the formation of LAPosome, thereby upregulating MHC Ⅱ to enhance immunological recognition. The Kla modification of IFI16 inhibits its interaction with DNA-PK and prevents the biogenesis of anti-infective cytokines to promote viral replication. KSHV can also induces the Kla modification of NAT10 to enhance stability of the RNA of KSHV, thereby facilitating viral replication. Furthermore, YTHDF1 and ALKBH5, the m6A writer and eraser, can also undergo Kla modifications, resulting in the mRNAs of IFNB1 and SFTSV NP stabilized to induce distinct effects.
Human cytomegalovirus (HCMV) infection exploits lactate to induce comprehensive Kla modification of host proteins, thereby promoting viral replication. The Kla modification of the viral DNA sensor interferon-γ-inducible protein 16 (IFI16) inhibits the recruitment of DNA-dependent protein kinase (DNA-PK), preventing IFI16-driven virus gene repression and cytokine induction, ultimately promoting viral replication [3]. Similarly, the RNA of Kaposi’s sarcoma-associated herpesvirus (KSHV) induces the Kla modification of N-Acetyltransferase 10 (NAT10) in host cells, enhancing the stability of the RNA of KSHV and increasing its translation efficiency, thereby facilitating viral replication [77]. Besides, viral infection can also induce the Kla modification of the N6-methyladenosine (m6A) reader YTHDF1, reducing its stability and promoting its degradation, thereby increasing viral mRNA stability and facilitating viral replication [44]. Furthermore, viral infection can promote the Kla modification of the m6A demethylase AlkB Homolog 5 (ALKBH5) and enhance its binding to the mRNA of IFNB in host cells. However, this effect leads to IFN-β upregulated, thereby inhibiting rather than promoting viral replication [43]. Thus, Kla modification of proteins in host cells might also activate anti-viral effect.
Beyond regulating the activity of RNA-associated proteins to either promote or inhibit viral replication, Kla modification can also modulate the activity of PRRs, reducing immune recognition and thereby facilitating infection. A recent study has shown that a high-lactate environment induced by infection promotes the Kla modification of cyclic GMP-AMP synthase (cGAS), abolishing its DNA-sensing capability. It prevents the activation of the cGAS-STING pathway, reducing immune recognition and impairing the capacity of pathogen clearance [78]. On the contrary, pathogen infected cells would enhance their anti-infective capabilities and promote cell survival in a high-lactate microenvironment through Kla modification of specific functional proteins. For instance, the Kla modification of rubicon autophagy regulator (RUBCN) enhances its interaction with vacuolar protein sorting 34 (VPS34), thereby promoting LAPosome formation and boosting the antibacterial capacity of macrophages [40].
In summary, the levels of lactate increase in pathogen-infected tissues, and pathogens leverage Kla modifications of host RNA-associated enzymes to stabilize their RNA and promote replication. One the one hand, the high-lactate microenvironment also enhances Kla modifications of PRRs, inhibiting their capacities of immune recognition and facilitating immune evasion of pathogens. On the other hand, the host employs Kla modifications of specific proteins in response to the high-lactate microenvironment to strengthen the capacity of pathogen clearance, thus protecting the host from infection. Therefore, Kla modification plays a crucial role in the dynamic interplay between host and pathogen.
The Kla modifications of functional proteins in neurological diseases
Neurological diseases are primarily categorized into four major types: neurodegenerative diseases, cerebrovascular diseases, neuroimmune diseases, and epilepsy [79,80,81,82]. Age-related risk factors significantly amplify the incidence of neurodegenerative diseases and cerebrovascular disorders in elderly populations, with these conditions collectively driving progressive disability and high mortality rates globally [83, 84]. According to the Global Burden of Disease data, the combined annual mortality from cerebrovascular disorders (6.5 million) and major neurodegenerative diseases (2.7 million) exceeds 9 million deaths globally, representing the third leading cause of death after cardiovascular diseases and cancers [83, 84]. Globally, approximately 6.6 million deaths annually are attributable to stroke, with acute mortality rates ranging from 10% to 20% for all stroke types and escalating to 30%-40% for hemorrhagic subtypes. Among survivors, over 50% experience disabling complications, including hemiplegia and aphasia [83, 85,86,87]. Besides, neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), though associated with lower acute mortality rates, pose more profound long-term harm [88,89,90].Particularly, ALS, being the most severe of the five major neurodegenerative diseases, still lacks an effective treatment, with a short survival period and a mortality rate close to 100% [91]. The evidence above highlights the significant threat of neurological diseases to human health, underscoring the urgency of research into their pathogenesis and treatments. Therefore, studies on the roles of Kla modifications of functional proteins in neurological diseases are being actively pursued, with Fig. 3 illustrating the impact of the Kla modifications of key protein in the diseases above.
The Kla modifications of functional proteins play both accelerative and suppressive roles in neurological diseases. The Kla-modified Tau can induce apoptosis and ferroptosis of neuron, thereby promoting the progression of AD. The Kla modification of Tufm can attenuate its interaction with Tomm40, inhibiting mitophagy to induce neuronal apoptosis. The vesicle-resident protein ARF can also be Kla-modified to inhibit the transmitting of healthy mitochondria from astrocytes to neurons, resulting in neuronal damage. On the contrary, the Kla modification of APP can inhibit the accumulation of Aβ, relieving the progression of AD. The Kla-modified SNAP91 can also promote vesicle formation and remodeling the shape of synapse to relieve anxiety disorder.
Recent studies have shown that the Kla modifications of functional proteins are closely related to the progression of AD. In the pathological tissues of AD, accumulated β-amyloid plaques (Aβ) excessively phosphorylate Tau, leading to the formation of neurofibrillary tangles (NFTs), which results in neuronal dysfunction or death [92,93,94]. A recent study demonstrated elevated lactate levels in the pathological tissues of AD compared to healthy controls, driving Kla modification of Tau at K331. This lactylation enhances Tau phosphorylation and cleavage by altering Tau’s conformation, increasing its susceptibility to GSK-3β and caspase-2. Additionally, lactylation at K331 competes with ubiquitination at the same lysine residue, reducing ubiquitin-dependent degradation of Tau via the ubiquitin-proteasome system, thereby promoting pathological Tau accumulation and accelerating AD progression [95]. Furthermore, Tau can also be lactylated at K677, which regulates iron metabolism-related factors such as NCOA4 and FTH1, promoting ferroptosis, exacerbating neuronal damage, impairing learning and memory abilities, thereby advancing the progression of AD [96]. The amyloid precursor protein (APP) in neurons of AD patients can also be lactylated. However, the Kla modification level of APP in neurons of patients is low, leading to disfunction of its degradation via the endosome-lysosome pathway. When the level of lactate further increases, the Kla modification of APP is enhanced, promoting its internalization from the plasma membrane to the endosome, followed by CD2AP-mediated endosome-lysosome degradation, which reduces Aβ production and accumulation, thereby improving neurocognition [97]. This study demonstrates that Kla modifications of functional proteins in neurons can also alleviate symptom of AD. However, the Kla modification of Tau plays a more significant role in facilitating AD progression.
The Kla modifications of functional proteins are also closely associated with stroke. ARF1, the protein involves in vesicular transport of astrocytes, can also undergo Kla modification while low-density lipoprotein receptor-related protein 1 (LRP1) is inhibited, which inhibits its function of transmitting healthy mitochondria from astrocytes to neurons, thereby leading to mitochondrial dysfunction in neurons and inducing stroke [98]. This study demonstrates that Kla modifications of functional proteins can regulate the intercellular transmission of organelles, thereby modulating the physiological and biochemical processes of neighboring cells.
The Kla modifications of functional proteins also play regulatory roles in other neurological diseases. Similar to the aforementioned diseases, total Kla modification levels of functional proteins are also elevated in pathological tissues of traumatic brain injury (TBI). Tufm, a key factor regulating mitophagy, has been found to be lactylated in damaged cells of TBI. The Kla modification of Tufm inhibits its interaction with Tomm40 on mitochondria and suppresses Tufm-mediated mitophagy, further promoting mitochondrial-induced neuronal apoptosis [99]. Additionally, lactate produced by anaerobic exercise can enhance the Kla modification of synaptosome-associated protein 91 (SNAP91) in neurons, modulating synaptic structure in the medial prefrontal cortex (mPFC) and promoting neuronal motility, thus alleviating anxiety disorder [100].
The abovementioned studies confirm that the Kla modifications of functional proteins play vital roles in astrocytes and neurons to induce neurological diseases.
The Kla modifications of functional proteins in cardiovascular diseases
Cardiovascular diseases (CVD) primarily include coronary atherosclerotic heart disease (CHD), hypertension-related hypertensive heart disease, heart failure (HF), arrhythmias, valvular heart disease, peripheral artery disease and aortic-related disorders [101,102,103,104]. CVD is the leading cause of death among the elderly and the most common cause of death globally, with an annual incidence of approximately 20 million cases, similar to that of malignant tumors [105]. However, the annual deaths of CVD reach 18.6 million, accounting for 32% of global deaths, which is significantly higher than the 10 million deaths caused by malignant tumors [105,106,107]. CVD progresses quickly with an extremely high mortality rate during the acute phase [108, 109]. Acute coronary syndrome (ACS), acute aortic dissection (AAD), malignant arrhythmias, and acute decompensated heart failure (ADHF) exhibit the highest mortality rates within 30 days from onset of diseases, ranging from 10% to 50% [110,111,112,113]. Even with treatment and successful recovery from the acute phase, patients may suffer from complications such as ventricular aneurysms, ventricular arrhythmias, renal insufficiency, and spinal ischemia, which significantly impact their quality of life [114]. Although the management of CVD is indispensable for lifesaving interventions and prognosis optimization, preventive strategies retain paramount importance in interrupting the pathogenic cascade at its upstream origins to fundamentally block disease progression. Therefore, studies on the pathogenesis of CVD provide a theoretical foundation for better prevention and treatment strategies.
As illustrated in Fig. 4, Kla modifications of functional proteins in high-lactate microenvironments play both promotive and inhibitory roles in CVD pathogenesis. Specifically, cellular stresses, such as hypoxia, inflammation, and metabolic disorders, contribute to the development of CVD, leading to myocardial ischemia, HF, and atherosclerosis [115,116,117,118,119]. Due to the upregulation of hypoxia-inducible factor 1-alpha (HIF-1α) and the activation of glycolytic pathways, the lactate level in microenvironment of CVD tissues is higher than that in normal conditions, resulting in Kla modifications of functional proteins, which induce both promotive and inhibitory effects on the onset and progression of CVD [120,121,122]. A recent study has indicated that Snail1 can be lactylated, which promotes its nuclear translocation, activating the TGF-β/Smad2 pathway, and induces endothelial-mesenchymal transition (EndoMT), leading to reduced coronary artery elasticity and impaired angiogenesis, thereby contributing to myocardial infarction [123]. In cardiomyocytes, prolyl 4-hydroxylase-β subunit (P4HB), a protein disulfide isomerase, undergoes Kla modification at K311 during DNA damage, enhancing its interaction with cyclooxygenase 2 (PTGS2), the key factor involves in synthesis of prostaglandin and regulation of oxidative stress. This interaction promotes mitochondrial reactive oxygen species (mitoROS) generation by activating the PTGS2-SH3GLB1 axis, which disrupts mitochondrial complex function and triggers NDP52-mediated mitophagy, exacerbating radiation-induced heart disease (RIHD) [124]. The effect above induces mitophagy, contributing to myocardial injury. Additionally, ischemia-reperfusion injury (IRI) after surgery can upregulate pyruvate dehydrogenase kinase 4 (PDK4), activating glycolysis and promoting the Kla modification of malate dehydrogenase 2 (MDH2), which damages myocardial mitochondrial function and induces ferroptosis of cardiomyocytes [125]. This effect can be mitigated by dexmedetomidine treatment, improving mitochondrial function and protecting cardiomyocytes.
The Kla modifications of functional proteins also play significant roles in the progression of cardiovascular diseases. The Kla modification of MDH2 and P4HB in cardiomyocyte can promote the accumulation of mitoROS to induce its ferroptosis and mitophagy. The Kla-modified α-MHC can also induce heart failure via regulating cell skeleton depolymerization. The Kla modifications of MeCP2 and Snail1 can also exerts protective and harmful effects to cardiomyocyte through modulating transcription of specific genes. Furthermore, the Kla modification of SA3K in fibroblasts could facilitate the survival of neighboring cardiomyocytes.
In high-lactate microenvironments, Kla modifications of functional proteins also play protective roles in cardiomyocytes. As previously mentioned, IRI causes an increase of intracellular lactate, leading to the Kla modification of serine protease inhibitor Serpina3k (SA3K), which enhances its stability to increase the protein level. The upregulated SA3K primarily protects cells from ischemia-reperfusion-induced apoptosis through paracrine signaling and by activating cardioprotective reperfusion injury salvage kinase and survivor activating factor enhancement pathways [126]. Moreover, Kla modification of α-myosin heavy chain (α-MHC) promotes its interaction with the cardiac myocyte structural protein titin, thereby maintaining the structure of cardiomyocytes. In patients with HF, the lactylation level of α-MHC is reduced, leading to compromised cardiac structure and function [127]. Furthermore, Kla modification also plays a crucial role in the prevention of cardiovascular diseases. Lactate generated during anaerobic exercise can induce the Kla modification of methyl-CpG binding protein 2 (MeCP2) to promote its interaction with histone H3 lysine 36 trimethylation (H3K36me3), resulting in chromatin accessibility increased and the transcriptional activity of the RUNX1 inhibited. The effect above facilitates the polarization of pro-repair M2 macrophages to prevent atherosclerosis [128].
Similar to the role of Kla modification in neurological diseases, Kla modifications of functional proteins exhibit Janus-faced roles in cardiovascular diseases. These findings provide important theoretical evidence for the prevention and treatment of cardiovascular diseases.
The Kla modifications of functional proteins in cancer
Since the mid-20th century, cancer has progressively emerged as the second leading cause of death worldwide, posing a persistent threat to global public health [129, 130]. Although the annual global incidence of cancer is comparable to that of cardiovascular diseases, with about 10 million deaths annually, lower than that of cardiovascular diseases, the incidence of cancer has been increasing annually due to longer life expectancies and detrimental lifestyle patterns [107, 131, 132]. Statistics reveal that the global annual incidence of new cancer cases tripled from 6.4 million in 1980 to 19.3 million in 2020, demonstrating a sharp increase in yearly diagnosis rates over the four-decade period [107, 133]. In contrast to cardiovascular diseases, which predominantly affect older populations, cancer is increasingly characterized by a younger-onset trend [107, 134, 135]. Emerging evidence suggests that this shift in epidemiological patterns may be linked to lifestyle-related risk factors prevalent among younger generations, including circadian rhythm dysregulation, prolonged exposure to high-sugar, high-fat and aflatoxin contaminated diets, and sustained psychosocial stressors such as occupational anxiety and social media-induced mental load [136,137,138,139,140]. Therefore, studies on cancer prevention and treatment have profound significance for preserving health security.
Figure 5 illustrates the multifaceted roles of lactate and Kla modifications in cancer progression, including metabolic reprogramming and immune evasion. The heightened proliferative activity of cancer cells drives an elevated demand for glucose, leading to significant upregulation of glucose transporter 1 (GLUT1) on the cell surface to enhance glucose uptake [141,142,143]. Concurrently, the Warburg effect, a metabolic hallmark of malignancies, induces marked activation of the glycolytic pathway in cancer cells, resulting in substantial lactate production despite adequate oxygen availability [35, 144, 145]. Lactate generated by cancer cells is partially exported into the extracellular spaces, where it suppresses CD8+ T cell proliferation, cytotoxic activity, and IFN-γ secretion, thereby impairing immune surveillance and fostering tumor immune evasion [146].
Oncoproteins and tumor suppressors can also undergo Kla modifications. The Kla-modified sites of proteins and their corresponding lactytransferases (red) and delactylases (blue) are presented. The Kla modifications of indicated proteins can induce radiotherapy and immunotherapy resistance, cell death resistance, production of lactate and activation of cell growth-related signaling pathways (red). Meanwhile, the Kla modifications of METTL16 and G6PD can also attenuate cancer progression via reducing ROS production and inhibiting ferroptosis (blue).
Hypoxia, a hallmark of cancer, significantly enhances lactate production via the Warburg effect, thereby driving Kla modifications. Under hypoxic conditions, cancer cells upregulate HIF-1α, activating glycolytic enzymes such as LDHA, leading to elevated lactate levels in the tumor microenvironment [144]. This lactate accumulation induces Kla modifications of functional proteins, affecting transcription factors, DNA repair proteins, and immune checkpoint proteins, thereby promoting tumor proliferation, metastasis, and immune evasion [144]. Hypoxia-induced lactylation plays a pivotal role in cancer progression by regulating key signaling pathways and metabolic reprogramming, with detailed mechanisms discussed later in this section [45, 147, 148].
Intracellularly, lactate accumulation activates HIF-1α-mediated transactivation of programmed death-ligand 1 (PD-L1), establishing additional immune tolerance mechanisms [149, 150]. Simultaneously, lactate functions as a signaling metabolite to stimulate NF-κB pathway activation, which drives epithelial-mesenchymal transition (EMT) and enhances vascular endothelial growth factor (VEGF) secretion [151, 152]. The processes above synergistically promote angiogenic remodeling of the tumor microenvironment (TME). Consequently, lactate serves as a critical regulator in both tumorigenesis and immune evasion. Given its pivotal role within the TME, Kla modifications of functional proteins in malignancies have been most extensively characterized. These Kla-mediated PTMs exert profound regulatory effects on multiple oncogenic processes, including tumor proliferation and metastasis, metabolic reprogramming, DNA damage repair, as well as resistance mechanisms to immunotherapy and targeted therapy [45, 147, 153,154,155,156,157].
The Kla modifications of oncogenic TFs are pivotal in driving tumor growth. A recent study revealed that in gastric cancer (GC) cells, TEA domain family member (TEAD) and its coactivator Yes-associated protein (YAP) undergo lactylation, enhancing the stability and transcriptional activity of the YAP-TEAD complex, thus activating the expression of aminoacyl-tRNA synthetase 1 (AARS1), which, beyond its canonical role in protein synthesis, functions as a lactyltransferase. AARS1 senses elevated lactate levels in the tumor microenvironment and translocates to the nucleus, where it further lactylates YAP and TEAD, reinforcing their interaction and promoting tumorigenesis in GC [148]. The E2 ubiquitin ligase ABC transporter family C member 1 (ABCF1) can also be Kla modified in GC, translocating into the nucleus to act as a TF, binding to the promoter of KDM3A, and promoting its transcription. The transactivation of KDM3A activates the KDM3A-H3K9me2-HIF-1α axis to enhance HCC growth [153]. Additionally, the Kla modifications of some transcriptional co-factors can activate TFs through enhancing their interactions. In HCC cells, the Kla modification of centromere protein A (CENPA) facilitates the formation of CENPA-YY1 complex, which activates the transcription of CCND2 and NRP2 genes, promoting tumor growth, metastasis, and angiogenesis in the TME [158]. The Kla modifications also promote the nuclear translocation of nuclear proteins without transcriptional activities. In pancreatic adenocarcinoma (PAAD), nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) is modified by Kla, enhancing its nuclear localization and enzymatic activity, thereby supporting the nuclear NAD+ salvage pathway and facilitating cancer progression [159]. Besides, the Kla modifications of DNA damage repair-associated proteins can enhance their activities to maintain genomic stability in cancer cells and promote tumorigenesis. In glioblastoma stem cells (GSCs), the Kla modification of X-ray repair cross-complementing protein 1 (XRCC1) promotes its binding with importin-α to facilitate its nuclear translocation, thus improving DNA damage repair capacity and radiotherapy resistance [147]. Furthermore, radiotherapy can promote the Kla modification of meiotic recombination 11 homolog (MRE11) by activating ATM phosphorylation, enhancing the DNA-binding ability of MRE11, mediating DNA damage repair to induce radiotherapy resistance [160].
Some recent studies have shown that Kla modifications in tumor cells can impact RNA modifications, thereby regulating the stability and translation of specific RNAs. This pathway also plays an essential role in tumorigenesis. In the TME of HCC patients, the Kla modification of insulin-like growth factor binding protein 3 (IGFBP3), the m6A reader YTH domain family protein 2 (YTHDF2) binding protein, can enhance its interaction with the mRNAs of PCK2 and NRF2, thereby transactivating the genes to promote lenvatinib resistance [156]. In colorectal cancer (CRC), the Kla modification of histone deacetylase 1 (HDAC1) reduces the levels of RNA demethylases fat mass and obesity-associated protein (FTO) and ALKBH5, increasing m6A modification on the mRNA of FSP1 to upregulate ferroptosis inhibitor protein ferroptosis suppressor 1 (FSP1), inhibiting ferroptosis and promoting tumor growth [161]. However, the Kla modifications of m6A-related enzymes may also inhibit tumor growth. The atypical m6A reader methyltransferase-like 16 (METTL16) can be lactylated in GC, promoting the m6A modification of the mRNA of FDX1, thus facilitating ferroptosis [162].
In addition to the previously mentioned m6A modification, mRNA can also undergo 5-methylcytosine (m5C) modification, which, analogous to m6A, has been demonstrated to regulate mRNA stability [163,164,165]. Moreover, m5C modifications also influence mRNA splicing and subcellular localization. In cholangiocarcinoma (CG), the m5C methyltransferase can be lactylated at K508 to significantly enhance its activity, which enhances the stability of the mRNA of GCLC, leading to the upregulation of GCLC, which induces the production of glutathione (GSH). The effect above can effectively suppress cellular ferroptosis by scavenging free radicals and reducing lipid peroxidation levels [166]. Furthermore, in CRC, NSUN2 could also be lactylated at K356, significantly enhancing its interaction with the mRNA of ENO1, and the upregulation of enolase 1, the protein encoded by ENO1, promotes glycolysis to generate more lactate and facilitate CRC progression [154].
Additionally, the Kla modifications of functional proteins also exert regulatory roles in RNA splicing and processing. High lactate microenvironment causes the Kla modification of polypyrimidine tract-binding protein 1 (PTBP1), the RNA processing protein, in GSCs, which inhibits its degradation by reducing its interaction with E3 ubiquitin ligase TRIM21. It elevates the expression of the mRNA of PFKFB4, the gene encoding key glycolytic enzyme, which further generates lactate, thus promoting glioma progression [155]. Another study suggests that in intrahepatic cholangiocarcinoma (ICC), nucleolin (NCL) undergoes Kla modification, which inhibits the alternative splicing of the precursor mRNA of MADD, thereby increasing its integrity and stability, upregulating mitogen-activated protein kinase-activated protein kinase (MADD) and activating the mitogen-activated protein kinase (MAPK) signaling pathway, facilitating ICC growth [167].
The Kla modifications of functional proteins can also directly regulate protein synthesis in cancer cells. In CRC, translation elongation factor eEF1A2 is lactylated to promote its mediation of ribosomal translation, which enhances total protein synthesis, leading to cell division and tumor proliferation [168].
Kla modifications also play critical roles in tumor immune evasion. In CRC, the lactylation of PD-L1 inhibits degradation via ubiquitin-proteasome pathway, and stabilizes cell surface PD-L1. Upregulated PD-L1 suppresses the activity of CD8+ T cells and attenuates their ability in impairing the immune surveillance and anti-tumor capabilities [45].
In addition to their previously described functions, Kla modifications of functional proteins play critical roles in maintaining cancer stemness, inducing cellular oxidative stress, and promoting cell cycle progression in tumors [169,170,171]. These studies demonstrate that while histone Kla modifications exert broad regulatory effects in malignancies, the Kla modifications of functional proteins are equally essential for tumorigenesis. The pleiotropic effects of histone Kla modifications, mediated through extensive gene network regulation, render them suboptimal therapeutic targets [33, 172]. In contrast, the Kla modifications of functional proteins exhibit superior target specificity due to their focused action on defined functional pathways, positioning them as more viable candidates for precision oncology. Future development of pharmacological agents targeting the Kla modifications of functional proteins holds promising therapeutic potential for clinical cancer management.
Conclusions and future perspectives
Kla modification, a recently discovered PTM, is currently under intensive investigations for its functions and mechanisms [173, 174]. Numerous studies have demonstrated that Kla modification plays a crucial role in the pathogenesis and development of various diseases [175,176,177]. Cellular stresses induced by inflammation, microbial infections, cellular damage, neurodegenerative diseases, cardiovascular diseases and the Warburg effect would facilitate lactate production and its accumulation in pathological tissues, resulting in significant upregulation of total Kla modifications of proteins involved in these diseases [78, 97, 98, 127, 145, 178]. Some early studies have shown that the Kla modifications of histone H3 and H4 subunits are the most prominent in total cellular proteins; however, due to their comprehensive regulatory effects on gene transcription, developing inhibitors targeting these modification sites could suppress broad transcriptional activities, making them unsuitable as drug targets [15, 17, 31, 179].
In a high-lactate microenvironment, the Kla modifications of functional proteins predominantly promote disease pathogenesis and progression through multiple mechanisms, including transactivation of pro-inflammatory cytokines, modification of specific mRNAs to enhance their stability and facilitate translation, induction of mitochondrial damage, enhancement of DNA damage repair in cancer cells, and participation in intracellular signal transduction pathways [38, 68, 147, 155, 167]. Generally, Kla modifications occur predominantly in pathological tissues with high lactate level, accelerating the disease progression [180,181,182]. However, as the organism possesses intrinsic mechanisms to counteract disease progression, Kla modifications may also inhibit or impede pathological development under certain conditions [98, 125]. Consequently, Kla modifications exhibit a dual regulatory role in disease contexts, either promoting or suppressing disease progression depending on specific cellular environments or pathological stages.
Mass spectrometry analysis of global protein Kla modifications and immunoblotting analysis have revealed that, in addition to well-documented histone Kla modifications, functional proteins exhibit substantial Kla modification abundance [78, 183]. Subsequent studies have corroborated that these Kla modifications of functional proteins play significant roles in disease progression (Fig. 6), which can be categorized as follows:
-
1.
TFs and their co-factors: We have collected and analyzed the studies of lactylation and discovered that this class of proteins represents the most prevalent targets of Kla modifications, second only to histones. During disease progression, Kla modifications on specific TFs and co-regulators facilitate the expression of pro-pathogenic genes, thereby driving disease pathogenesis and advancement.
-
2.
DNA damage repair-associated proteins: In diseases such as cancer, the genome experiences DNA replication stress, leading to damage or even strand breaks that ultimately promote cell death [184,185,186]. It necessitates the recruitment of DNA damage repair proteins to restore genomic integrity [187,188,189]. Notably, Kla modifications on DNA damage repair-associated proteins facilitate their nuclear translocation and enhance DNA-binding affinity, thereby promoting efficient damage repair and ensuring cellular survival [147, 160]. Paradoxically, this pro-survival mechanism also confers tumor resistance to radiotherapy in clinical contexts.
-
3.
RNA processing-related proteins: The m6A and m5C RNA modifications are identified on the c-terminal of coding DNA sequences (CDS) and 3’ untranslated regions (UTRs) of mRNAs, which could enhance the stabilities of specific proteins and facilitate their translation [190,191,192]. Several studies have confirmed that enzymes involved in m6A and m5C RNA modifications can be significantly Kla-modified, leading to enhanced stability or increased translation efficiency of specific mRNAs [156, 166]. Besides, the Kla modification of RNA-splicing-associated enzyme can also facilitate the expression of oncoproteins, resulting in the activation of MAPK signaling pathway to promote cancer progression [167]. The effects above upregulate specific proteins via enhancing the stability of mRNAs or promoting their translation, thus accelerating disease progression.
-
4.
Metabolic enzymes: Intracellular lactate accumulation primarily results from activated glycolytic pathways [193,194,195]. The resultant high-lactate microenvironment further induces Kla modifications on glycolysis-related enzymes [41, 169]. The Kla modifications of these enzymes enhance glycolytic activity, leading to increased lactate production and establishing a self-reinforcing positive feedback loop. This cycle amplifies both lactate levels and Kla modifications on other functional proteins, thereby accelerating disease progression.
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5.
Mitochondrial proteins: Mitochondria not only produce energy through oxidative phosphorylation but are also central to the intrinsic pathway of apoptosis [196,197,198,199]. The Kla modifications of mitochondrial proteins enhance their oxidative phosphorylation activity, leading to excessive ROS production, while simultaneously promoting mitochondrial-mediated apoptotic pathways [99, 124]. Both effects synergistically induce tissue damage.
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6.
Other functional proteins: The Kla modifications also target ubiquitin ligases, protein synthesis machinery components, and signaling transducers, thereby exerting regulatory control over disease pathogenesis and progression [20, 42, 168]. It is deemed that a considerable number of functional proteins may harbor Kla modifications, yet this field remains largely uncharted, presenting a vast research frontier that urgently demands further systematic exploration.
Functional proteins undergo Kla modifications during the processes of various diseases, including inflammation, infectious diseases, neurological diseases, cardiovascular diseases and cancer. The Kla modifications can facilitate the nuclear translocation of TFs, and enhance their interactions with promoters to transactivate specific genes. The Kla modifications can also promote DNA damage repairing to induce radiotherapy resistance of cancer cells. Besides, the Kla modifications of RNA methylation-related enzymes can also stabilize mRNAs, facilitate their translations, or promote RNA splicing, thus accelerating protein synthesis. The Kla-modified metabolic enzymes can constantly activate glycolysis to promote lactate production and form the lactate positive feedback loop. Moreover, the Kla modifications of some mitochondrial proteins can cause the accumulation of mitoROS, and trigger mitochondria-mediated cell death. In addition to the effects above, the Kla modifications of specific proteins can also regulate their synthesis, degradation and activities to modulate signal transduction.
For scientists interested in exploring the Kla modifications of proteins, several studies provide comprehensive methodologies and reagents for detecting and characterizing them. LC-MS/MS has been instrumental in identifying Kla sites, as demonstrated in the initial discovery of histone lactylation [7]. Additionally, anti-L-Kla antibodies are widely used for immunoblotting, immunoprecipitation, and immunofluorescence to detect Kla modifications across histone and non-histone proteins. Anti-L-Lactyl Lysine Rabbit mAb (PTM-1401RM, PTM Bio, Chicago, IL, USA) is currently a highly cited and high-quality antibody used for lactylation detection [98, 160, 200]. High-throughput lactylome profiling and CRISPR-based gene editing further enable the study of Kla dynamics and functional roles of lactyltransferases [78]. These methodologies, including quantitative proteomics, site-specific mutagenesis, and chromatin immunoprecipitation, offer robust tools for investigating molecular mechanisms and therapeutic potential of Kla modifications in various diseases.
Although studies on the Kla modifications of functional proteins have been rapidly advancing, the aspects below remain poorly understood. Firstly, while the Kla modifications of many functional proteins have been identified through LC-MS/MS, the biological effects of these modifications remain unclear. Secondly, the writers and erasers governing lactylation and delactylation of regulatory proteins remain incompletely characterized. Identifying these regulatory enzymes and elucidating their substrate specificity will facilitate the development of therapeutic targets for diseases above. Thirdly, proteins susceptible to Kla modification under pathological conditions with high lactate levels are likely to exhibit functional synergies in cellular stress adaptation mechanisms. Deciphering these cooperative interactions could deepen our understanding of Kla modifications in diseases. Finally, in contrast to histone Kla modifications that drive broad transcriptional reprogramming, Kla modifications of functional proteins often exert more discrete functional effects. Targeting Kla modifications of functional proteins may enable precision therapeutics with enhanced efficacy and reduced adverse effects [201].
Despite the emerging significance of Kla modifications in disease pathogenesis, its clinical translation faces multiple challenges. The dynamic regulation of lactylation, driven by variable lactate levels across tissues and disease states, hinders the development of consistent biomarkers [202]. Additionally, the broad specificity of Kla modifications across diverse proteins complicates pinpointing critical modification sites for precise therapeutic targeting [203]. Current detection methods, such as mass spectrometry, remain technically complex and impractical for routine clinical use, necessitating simpler assays [204]. Furthermore, the incomplete understanding of functional consequences of Kla modifications limits the design of precise interventions [205]. Finally, therapeutic modulation of lactylation lacks specificity and clinical validation, requiring further research to unlock its potential in practice [206].
Although Kla-targeted therapies show promising therapeutic potential, they remain in nascent stages of development. Further mechanistic investigations and translational studies are imperative to advance these strategies toward clinical implementation, ultimately expanding the arsenal for disease intervention.
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Acknowledgements
We would like to acknowledge Dr. Chen Pan from Zhejiang University for his advice.
Funding
This work was supported by R&D Program of Zhejiang Province under Grant 2024C03142 and 2025C02111, National Natural Science Foundation of China under Grant 82103397 and 82571659.
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Conceptualization: Y.L., X.G., X.H., S.Z. and L.Z. Reference collection: Y.L., X.G. and Q.Y. Figure composition: Y.L. Writing-original draft: Y.L. Writing-revised manuscript: Y.L., P.F. Writing-review and editing: Y.L. and L.Z.
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Liu, Y., Guo, X., Hu, X. et al. Lysine lactylation in diseases: beyond histone lactylation. Cell Death Dis 17, 55 (2026). https://doi.org/10.1038/s41419-025-08223-6
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DOI: https://doi.org/10.1038/s41419-025-08223-6
