Histone lactylation: a novel epigenetic bridge linking cellular metabolism to benign and malignant gynecological diseases

Abstract

Lactic acid modification of histones represents an emerging post-translational modification that establishes a critical link between cellular metabolic reprogramming and epigenetic regulation through the covalent binding of lactic acid to histone lysine residues. In recent years, the mechanisms underlying this modification in the pathogenesis of various diseases have been progressively elucidated, revealing its extensive biological impact and potential clinical translational value. As research progresses, the functional role of histone lactylation in gynecological diseases has become increasingly evident, offering a novel epigenetic perspective for deciphering the pathogenesis of gynecological-related disorders. This review outlines the mechanisms underlying histone lactylation and focuses on its regulatory role in common benign and malignant gynecological diseases. The malignant diseases discussed include ovarian, endometrial, and cervical cancers, while the benign conditions include endometriosis and polycystic ovary syndrome. Furthermore, it undertakes an analysis of the therapeutic potential of histone lactylation modifications and reviews emerging targeted therapeutic strategies. These include targeting lactate production, lactate transport, lactylation-associated enzymes, or downstream effectors, highlighting their potential to intervene in disease progression. The present study aims to systematically elucidate the core value of histone lactylation as a novel epigenetic link between metabolism and gynecological disease pathogenesis. In addition, it provides clear research directions and robust theoretical support for developing targeted therapeutic strategies based on lactylation modifications.

Background

In recent years, with the continuous advancement of proteomics research, protein post-translational modifications (PTMs), as critical molecular links connecting cellular metabolism and epigenetic regulation, have been shown to play vital roles in expanding protein functional diversity and maintaining signal network homeostasis [1]. As an emerging class of PTMs, lactylation is directly generated from the metabolic product lactate, dynamically reflects cellular metabolic status, and retains the reversible property of epigenetic regulation [2]. Given its unique biological functions in embryonic development, gene transcriptional regulation, tumorigenesis, and the acquisition of drug resistance, lactylation has rapidly become a research hotspot in the life sciences [3–6].

In 2019, scientists first discovered lactate-mediated histone lysine lactylation as a novel epigenetic modification, sparking in-depth research into its writers, readers, and erasers [7]. Ever since it’s discovery in 2019, the mechanisms underlying histone lactylation are progressively being elucidated in oncology [8], respiratory diseases [9], neurological disorders [10], and inflammation [11], and represents a potential novel therapeutic target. It is noteworthy that mounting evidence in recent years has indicated a close association between histone lactylation modifications and the onset and progression of gynecological diseases. Nevertheless, the academic community has yet to systematically integrate and review research in this field.

To this end, this review systematically summarizes histone lactylation—a novel epigenetic modification—in relation to major benign and malignant gynecological diseases for the first time. The present study comprehensively elucidates the molecular mechanisms of histone lactylation, further explores its regulatory role in benign and malignant gynecological diseases, and outlines targeted therapeutic strategies for this modification, emphasizing its clinical translational potential. This study fills the research gap in this field and provides a crucial theoretical reference for subsequent investigations into the metabolic-epigenetic crosstalk mechanisms in gynecological diseases as well as the corresponding targeted therapeutic strategies.

Epigenetics and histone modification

Epigenetics is the study of molecular biological processes that achieve reversible, dynamic regulation of gene expression through mechanisms such as DNA methylation, histone modifications, and non-coding RNA regulation, without altering DNA sequences [12]. These processes influence cellular phenotypes and functions and can be inherited under specific conditions, highlighting the intricate and precise network of gene regulation [13]. Among these, histone modifications, as a crucial mechanism for gene expression regulation, represent a particularly active area of research in both biological and medical domains. Histones constitute the core components of chromatin, primarily categorized into two types: core histones (H2A, H2B, H3, H4), where four core histones each form two molecules to create an octamer, constituting the core scaffold of the nucleosome; and linker histones (H1), located between nucleosomes, responsible for stabilizing nucleosome structure and facilitating further chromatin compaction (Fig. 1) [14]. Histones are highly conserved basic proteins with diverse post-translational modifications occurring on their N- and C-terminal tails, including acetylation, methylation, phosphorylation, ubiquitination, ADP-ribosylation, glycosylation, lactylation, and isonicotinylation [15, 16]. These modifications alter the charge and structure of histone tails, affecting their ability to bind to DNA and thereby regulating chromatin structural states and gene transcriptional activity [17].

Fig. 1.

Schematic diagram of histone modifications. This figure illustrates the major post-translational modification (PTM) landscape on the N-terminal tails of core histones (H2A, H2B, H3 and H4). Four types of modification are exemplified: methylation (Me), acetylation (Ac), ubiquitination (Ub) and phosphorylation (P). The site distribution of each modification on specific amino acid residues of histones is labelled — namely lysine (K), arginine (R), serine (S) and threonine (T). The histone tails protrude from the nucleosome core and serve as targets for various PTMs. These modifications participate in epigenetic processes such as chromatin remodeling and gene transcription regulation by establishing the ‘’histone code’’

However, abnormal dysregulation of histone modifications can contribute to the onset and progression of disease by disrupting the balance between transcriptional activation and repression [18]. In the field of oncology, abnormalities in histone acetylation and methylation modifications are particularly prevalent [19, 20]. Dysregulated histone modifications also play a critical role in immune system disorders [21]. In addition to the aforementioned modifications, other types of histone modifications have been shown to be associated with the onset and progression of diseases. For instance, histone lactylation responds to changes in cellular metabolic states and plays a role in pathological processes, including macrophage polarization, inflammation regulation, and tumor progression [7]. Meanwhile, abnormal histone crotonylation is associated with acute kidney injury and renal fibrosis [22, 23]. Therefore, abnormal histone modifications are not limited to a single disease type, but rather represent a common epigenetic event in the development of various diseases.

It is clear that histone modifications play a key role in disease research and clinical management. From a mechanistic perspective, they shed light on the molecular pathways through which environmental and genetic interactions trigger disease. Diagnostically, histone modification biomarkers and histone deacetylases (HDAC) activity assays can be used for the early screening, staging and prognostic assessment of tumors [4, 24]. Therapeutically, drugs that target histone modification enzymes are being increasingly explored [25]. A deeper understanding of the regulatory mechanisms of histone modifications is crucial for refining disease pathogenesis, improving diagnosis and prognosis, and advancing targeted therapies.

The landscape of histone lactylation

Advances in mass spectrometry technology have led to an expansion in the types and sites of PTMs. In 2019, Zhang et al. [7] at the University of Chicago discovered a histone modification mediated by lactic acid: histone lactylation. The discovery of histone lactylation pioneered a new paradigm where metabolites directly regulate epigenetics. This modification is directly mediated by lactate molecules, covalently attaching to lysine residues on histones, thereby tightly linking cellular metabolic states to gene expression programs [26]. Its core mechanism revolves around lactate production and activation, the action of modifying enzymes, and the coordinated regulation of gene expression (Fig. 2).

Fig. 2.

The metabolic origin and dynamic regulation of histone lactylation. Glucose enters the cytoplasm through glucose transporters (GLUTs), such as GLUT1, GLUT3, and GLUT4, and is metabolized by glycolysis to pyruvate, which is then converted to lactate by LDHA. Lactate then translocates into the nucleus, where ACSS2 and GTPSCS catalyze its conversion to lactyl-CoA. Lactyl-CoA serves as the donor for histone lactylation. In the nucleus, unmodified chromatin is first recognized by lactylation “writers” such as p300/CBP, HBO1, and GCN5, which transfer the lactyl group (La) to histone tails and generate lactylated chromatin. Lactylated histone marks can then be recognized by “readers,” including BRG1, TRIM33, and DPF2, leading to altered chromatin structure and transcriptional regulation. Conversely, “erasers,” such as HDACs and SIRT1–3, remove La marks from histones and restore the unmodified chromatin state. This writing–reading–erasing process constitutes the dynamic regulatory cycle of histone lactylation

Occurrence of lactic acid and histone lactylation

Lactic acid is an important metabolic product of glycolysis; it is produced both during anaerobic glycolysis under hypoxic conditions and during abnormal glycolysis in tumor cells under aerobic conditions. Under hypoxic conditions, cells primarily break down glucose into pyruvate through anaerobic glycolysis; pyruvate is then reduced to lactic acid by lactate dehydrogenase [27]. Even when oxygen is readily available, tumor cells tend to derive energy through glycolysis rather than mitochondrial oxidative phosphorylation, a phenomenon known as the Warburg effect. This effect increases glucose uptake and glycolytic flux, which promotes the production and accumulation of large amounts of lactate in the tumor microenvironment (TME). This effect is a key feature of tumor metabolic reprogramming and an important metabolic basis for histone lactylation in tumors [28].

Research indicates that histone lactylation occurs in a manner similar to histone acetylation: when endogenous or exogenous lactate accumulates to a certain concentration, it acts as a precursor to induce this modification [7]. Lactate can be converted into lactyl-CoA by enzymes involved in lactyl-CoA synthesis. Previous studies have demonstrated that acyl-CoA synthetase short-chain family member 2 (ACSS2) can function as a lactyl-CoA synthetase and catalyze the conversion of lactate to lactyl-CoA [29]. In addition, the nuclear GTP-specific succinyl-CoA synthetase complex has also been reported to possess lactyl-CoA synthetase activity [30]. Subsequently, intracellular enzymes can use lactyl-CoA as a donor to transfer lactyl groups to lysine residues on histones, thereby inducing histone lactylation. This modification can alter chromatin status and affect the transcription of related genes, thereby participating in the regulation of downstream signaling pathways and promoting diverse biological processes [4, 31].

Key enzymes involved in histone lactylation

Similar to post-translational modifications such as acetylation, histone lactylation is a reversible covalent modification. Its occurrence, removal, and functional regulation primarily depend on histone-modifying enzymes and their corresponding cofactors, which are categorized into three major classes: “writers”, “erasers”, and “readers” (Table 1). These three groups of proteins collectively regulate the dynamic changes of histone lactylation modification and its biological functions.

Table 1.

Enzymatic regulatory systems modified by histone lactylation

Category	Histone-modifying enzyme type	Family / representative proteins	Regulatory modification type	Representative reported lactylation sites	Main function	Refs.
Writers	Histone lactyltransferases	p300/CBP family: p300, CBP	Lactylation writing	H3K18la; H4K12la; pan-histone Kla	Use lactyl-CoA as the donor to transfer lactyl groups onto histone lysine residues, thereby establishing histone lactylation marks.	[7, 32, 33]
	Histone lactyltransferases	GNAT family: GCN5/KAT2A	Lactylation writing	H3K18la	Catalyze histone lysine lactylation and connect lactate-derived metabolic signals with transcriptional activation.	[29, 34]
	Histone lactyltransferases	MYST family: HBO1/KAT7	Lactylation writing	H3K9la	Catalyze site-specific histone lactylation and regulate chromatin-associated transcriptional programs.	[35]
Erasers	Histone delactylases	HDAC family	Delactylation	H3K18la; H4K15la	Remove lactyl groups from histones and reverse lactylation-mediated transcriptional regulation.	[34, 36]
	Histone delactylases	SIRT family	Delactylation	H4K8la; H4K16la; H3K9la; H3K18la	Mediate NAD+-dependent delactylation and contribute to the reversible control of histone lactylation.	[37–41]
Readers	Histone lactylation recognition proteins	BRG1	Lactylated histone recognition	H3K18la	Recognize lactylated histone marks and mediate downstream chromatin remodeling or transcriptional responses.	[31]
	Histone lactylation recognition proteins	TRIM33	Lactylated histone recognition	H3K18la	Recognize lactylated histone marks and link lactylation signals to gene transcription.	[42]
	Histone lactylation recognition proteins	DPF2	Lactylated histone recognition	H3K14la	Recognize H3K14la and participate in transcriptional regulation.	[43]

Writers

“Writers” are responsible for adding specific modification groups to histones. Among these, histone acetyltransferases (HATs) are key members of this family. The most extensively studied classical “writers” include p300 and its homologue, the CREB-binding protein (CBP) [44]. P300/CBP catalyses the formation of lactylation modifications by transferring a lactyl group from lactyl-CoA to specific lysine residues on histone H3 [7]. Furthermore, it has been demonstrated that other members of the HAT family possess catalytic functions. For instance, HBO1, a member of the MYST family, catalyses H3K9la and regulates the expression of downstream genes [35]. GCN5, belonging to the GNAT family, is specifically catalysed at the H3K18 site by IL-1β signals [45].

Histone lactylation and acetylation are in a close competitive relationship at the regulatory level. Both processes target conserved lysine residues in the N-terminal tail of histones, including core sites such as H3K9, H3K18 and H4K12 [46], and they share members of the HAT family, such as p300 and CBP, as catalytic enzymes. Consequently, they compete directly for substrate binding and site occupancy. Under physiological conditions, intracellular concentrations of acetyl-CoA are significantly higher than those of lactyl-CoA and acetylation dominates and maintains gene transcription [47]. However, under pathological conditions characterized by metabolic reprogramming and enhanced glycolysis, increased lactate production leads to elevated lactyl-CoA levels [48]. Lactyl groups may competitively occupy the same lysine residues, thereby altering the relative modification balance between acetylation and lactylation and initiating lactate metabolism-associated transcriptional programs. This competitive modification pattern, involving the same lysine sites and overlapping enzymatic systems, provides an important basis for lactylation-associated metabolic transcriptional regulation.

This raises a key scientific question: How do these modifying enzymes achieve such precise selectivity between the highly similar processes of acetylation and lactylation? Acetyl-CoA and lactyl-CoA differ slightly in chemical structure. The latter has one additional carbon atom and one hydroxyl group compared to the former. These differences result in a longer carbon chain and a more complex structure for lactyl-CoA. Studies on enzyme reaction kinetics and structural biology indicate that the acyltransferase activity of p300 decreases as the carbon chain length of acyl-CoA increases [49]. Combined with the fact that acetyl-CoA is far more abundant than lactyl-CoA, this suggests that under steady-state metabolic conditions, acetylation is more likely to be the default mode of histone lysine modification [49].However, intracellular substrate competition is not static. First, metabolic reprogramming serves as a central driving force. In cells with active glycolysis, for example, an increase in the [lactyl-CoA]/[acetyl-CoA] ratio caused by lactate accumulation leads to the preferential utilization of lactyl-CoA by p300/CBP [30]. Next, the structural plasticity of the enzyme active site enables it to accommodate both acetyl-CoA and lactyl-CoA, thereby providing a structural basis for substrate selection [49]. The p300 substrate binding pocket can accommodate the slightly larger lactyl-CoA. Its polar amino acid residues form additional hydrogen bonds with lactyl-CoA’s hydroxyl group, improving recognition specificity [50]. Additionally, the spatial microenvironment reinforces selectivity. For instance, ACSS2, a lactyl-CoA synthase, physically binds to KAT2A, which increases the effective concentration of lactyl-CoA and promotes histone lactylation [29]. Finally, the post-translational modifications of the enzymes themselves can alter substrate specificity through conformational changes [50].

Erasers

“Erasers” remove modified groups from histones, restoring them to their original state. The currently known deacetylases are primarily classified into two major families: Zn²⁺-dependent HDAC and NAD⁺-dependent deacetylases (sirtuins) [51, 52]. HDAC1-3 and SIRT1-3 exhibit strong delactylation activity and serve as the primary “erasers” for histone lactylation modification [51]. Among these, HDAC1-3 is the most potent lysine deslactase in vitro. Further studies revealed that HDAC1/2 had a limited ability to delactate under in vitro conditions, while HDAC3 had the strongest ability to delactate [36]. Intracellularly, HDAC1 and HDAC3 are the main “eraser” of histone lactatation modification [36]. Unlike Zn²⁺-dependent HDAC, however, sirtuins recognize lactate strictly in dependence on NAD⁺ concentration, and their activity is directly regulated by the energy status of cells [53]. This establishes sirtuins as pivotal nodes that link NAD⁺ metabolism to lactate-induced epigenetic regulation. SIRT1 is primarily found in the nucleus, where it controls the overall level of lactate. However, SIRT3, which is localized in the mitochondria, has significant catalytic efficiency on H4K16la [37].

Readers

“Readers” are proteins that can recognize and bind to specific modifying groups. This regulates gene expression and other cellular processes. Currently, validated readers for histone lactylation mainly include three classes, which identify specific lactylation sites through different domains. Brg1, as the first reported lactylated reader, recognizes H3K18la through its C-terminal bromodomain, recruiting chromatin remodeling complexes to activate pluripotency gene expression [31]. Furthermore, a research team identified another reader for histone lysine lactylation—TRIM33—using AlphaScreen technology. They confirmed that the bromodomain in the TRIM33 protein exhibits sub-micromolar binding affinity for histone lysine lactylation modifications [42]. DPF2 is another lactylated histone reader identified after BRG1 and TRIM33. DPF2 specifically recognizes H3K14la through its PHD finger domain, promoting the transcription of tumor-associated genes [43].

The recognition mechanisms of lactylation readers have revealed the unique structural basis of this modification. Compared with the acetyl group (-CO-CH₃), the additional hydroxyl group introduced by the lactyl group (-CO-CH(OH)-CH₃) is likely the key determinant for specific recognition. First, reader proteins can use the hydroxyl group on lactate to form an additional hydrogen bond network, which acetylation modification cannot provide. For instance, the bromodomain of TRIM33 may increase binding specificity by interacting with specific amino acid residues in the pocket and the lactate hydroxyl group [42]. Second, the lactyl group introduced by lactylation is longer and contains an additional hydroxyl group, thereby altering the local polarity. This prompts potential readers to evolve more spatially inclusive or polarity-specific binding pockets. This stabilizes the modified lactylated side chain while excluding other acylation modifications [42, 54].Furthermore, the identified readers include ATP-dependent chromatin remodeling factors (Brg1), bromodomain-containing E3 ubiquitin ligases (TRIM33), and proteins with PHD/C2HC zinc finger structures (DPF2). This diversity indicates that lactylation recognition is not limited to one domain type and that multiple chromatin-associated modules can detect lactylation signals. Research on histone lactylation readers is still in its early stages, with only a few molecules having been identified thus far. This severely limits our comprehensive understanding of the lactylation signaling cascade because current discoveries represent only the tip of the iceberg. Numerous potential readers remain to be discovered.

In summary, histone lactylation has established a relatively well-defined dynamic regulatory system consisting of “writers,” “erasers,” and “readers.” p300, HBO1, GCN5, and other enzymes act as “writers” to catalyze lactylation; members of the HDAC and SIRT families function as “erasers” to remove this modification; and BRG1, TRIM33, and DPF2 serve as “readers” that recognize lactylation signals and mediate downstream biological effects. Through the coordinated actions of these three classes of regulators, histone lactylation can convert cellular metabolic signals into epigenetic instructions, thereby regulating chromatin status and target gene transcription and playing important roles in pathological processes related to immune phenotypic switching, DNA damage repair, and metabolic reprogramming. Notably, histone lactylation is not an isolated epigenetic mark; rather, it can undergo cross-regulation with acetylation [55], methylation [56], ubiquitination [57], SUMOylation [58], and other modifications, thereby jointly influencing chromatin accessibility or compaction and specific gene expression programs. Thus, the biological effects of histone lactylation do not result from a single linear pathway, but rather from a dynamic regulatory network formed by the combined effects of metabolic state, enzyme activity, substrate availability, and crosstalk among various post-translational modifications.

The role of histone lactylation in benign and malignant gynecological diseases

In both benign and malignant gynecological diseases, metabolic reprogramming, local hypoxia, chronic inflammation, and abnormal endocrine microenvironments can promote lactate production and accumulation, thereby providing an important metabolic basis for histone lactylation. In gynecological malignancies, Warburg effect–mediated enhancement of glycolysis can increase lactate levels in the TME and induce histone lactylation, thereby affecting tumor cell proliferation, migration, immune escape, and therapeutic resistance. In benign gynecological diseases such as endometriosis (EMS) and polycystic ovary syndrome (PCOS), histone lactylation may also respond to inflammatory, endocrine, and metabolic abnormalities, regulate the transcription of related genes, and participate in disease progression. Therefore, histone lactylation may represent an important mechanism linking metabolic abnormalities to epigenetic regulation in gynecological diseases.

Ovarian cancer

Ovarian cancer (OC) is the third most common gynecological malignancy worldwide and the leading cause of death among gynecological cancers [59]. Studies have confirmed that the expression levels of lactylation-related genes are significantly correlated with tumor stage and prognosis in OC patients. Chao et al. [60] conducted a study on epithelial ovarian cancer (EOC) and found that both the total lactylation level and the level of histone H3 lysine 18 lactylation (H3K18la) in EOC tissues were significantly higher than those in normal ovarian tissues. Moreover, as the pathological stage of EOC advanced, the level of H3K18la showed a gradual upward trend, suggesting that high H3K18la expression may be closely associated with poor prognosis in EOC patients. Further survival analysis revealed that EOC patients with high H3K18la expression had significantly shorter overall survival and progression-free survival. Thus, H3K18la can serve as a key independent marker for poor prognosis in EOC patients. In addition, histone lactylation may also be involved in the occurrence and development of EOC by enhancing the migration ability of tumor cells and inducing platinum-based drug resistance.

As described above, Warburg effect–mediated lactate accumulation is an important consequence of tumor metabolic reprogramming. Lactate can reshape immune cell function by inducing histone lactylation, thereby promoting the formation of an immunosuppressive microenvironment and contributing to OC progression. Sun et al. [61] found that lactate can induce the polarization of macrophages toward the M2 phenotype in a dose-dependent manner via the macrophage surface receptor Gpr132. Concurrently, it promotes histone H3 lysine 18 lactylation (H3K18la) in macrophages. H3K18la directly binds to the promoter region of CCL18 and activates its transcription, leading to massive secretion of CCL18 by M2-type macrophages, which further enhances the proliferation and migration of OC cells. In vivo experimental validation showed that knockdown of Gpr132 or blocking of CCL18 significantly inhibited tumor growth and liver metastasis. Lactate dehydrogenase B (LDHB), a key glycolytic enzyme that catalyses the reversible conversion between pyruvate and lactate, is highly expressed in tumors that depend on aerobic glycolysis [62]. Hu et al. [63] demonstrated that LDHB promotes lactate production in OC by regulating glucose metabolism, which in turn induces H3K18la at the promoter region of programmed death-ligand 1 (PD-L1). This modification activates the transcription and expression of PD-L1. Highly expressed PD-L1 binds to programmed death-1 (PD-1) on the surface of T cells, inhibiting T cell proliferation, the secretion of killing-related factors, and the release of immune activation factors—thereby enabling OC cells to achieve immune evasion. Inhibiting LDHB or blocking the LDHB-mediated H3K18la/PD-L1 pathway can restore the anti-tumor immune function of T cells. Furthermore, a recent study on high-grade serous ovarian carcinoma (HGSOC) has found that FOXK1 promotes lactate accumulation by regulating glycolipid metabolism, thereby inducing histone lactylation modification of TOX [64]. These findings suggest that the FOXK1-TOX-lactylation axis could be a promising target for immunotherapy in HGSOC. The aforementioned studies reveal the critical regulatory role of histone lactylation in OC immune evasion.

Drug resistance is a major cause of poor prognosis and cancer recurrence in OC patients. In particular, resistance to platinum-based drugs and poly (ADP-ribose) polymerase inhibitors severely limits the clinical therapeutic efficacy of OC [65, 66]. Studies have shown that histone lactylation modification can directly mediate therapeutic resistance in OC by regulating pathways such as DNA damage repair and oncogene transcription. Homologous recombination (HR) repair is one of the core mechanisms underlying platinum resistance in OC patients. Cisplatin exerts its anti-tumor effect by inducing DNA double-strand breaks, while efficient HR repair can eliminate cisplatin-induced DNA damage, leading to cisplatin resistance in cancer cells [67]. Sun et al. [68] found that elevated H3K9la in platinum-resistant OC directly activated the transcription of RAD51 and BRCA2, thereby promoting homologous recombination (HR) repair. In parallel, RAD51 itself could undergo lactylation at lysine 73, which enhanced its DNA repair function and mediated cisplatin resistance. H3K9la and RAD51K73la shared the same upstream regulatory enzyme, GCN5, and inhibition of GCN5 simultaneously attenuated both histone and non-histone lactylation signals, thereby restoring cisplatin sensitivity. This study suggests the existence of a coordinated regulatory network involving “histone lactylation–non-histone lactylation–DNA repair” in OC. Super-enhancers (SEs) are cis-regulatory elements with potent transcriptional activation functions that recruit transcription factors to drive oncogene expression, contributing to tumor progression and drug resistance [69]. Lu et al. [70] discovered that lactate accumulation in OC drug-resistant cells induces elevated H4K12 lactylation. H4K12la enhances Nira-SE activity by recruiting the transcription factor MYC to the RAD23A promoter region, thereby driving RAD23A transcription. This increases the capacity for DNA damage repair, reduces niraparib-induced DNA damage and ultimately leads to niraparib resistance in OC cells. In patient-derived organoids and subcutaneous xenograft models in nude mice, knocking down RAD23A or inhibiting H4K12la using the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) significantly restored OC cell sensitivity. Furthermore, a recent study revealed that glycolysis-induced lactate accumulation in OC cells leads to elevated levels of histone H3 lysine 18 lactylation (H3K18la) [71]. H3K18la enrichment at the TRA2A promoter enhances transcription of the gene. TRA2A acts as a splicing factor that binds to STIL pre-mRNA via its RRM domain, regulating its alternative splicing and generating the STIL-L subtype. This ultimately inhibits ferroptosis and induces cisplatin resistance.

Notably, beyond the aforementioned targeted small-molecule inhibitors, bioactive components from traditional Chinese medicine (TCM) have also been validated to exert anti-OC effects by regulating histone lactylation pathways. Salvia miltiorrhiza (Danshen), a classic TCM herb, has a lipophilic bioactive constituent—tanshinone I—that has been shown to possess anti-inflammatory, antibacterial, and broad-spectrum anti-tumor activities [72]. Jin et al. [73] demonstrated that tanshinone I inhibits transcription factors FOXK1/2, which in turn downregulates the expression of key glycolytic enzymes to reduce lactate production; decreased lactate levels further diminish histone H3 lysine 18 lactylation (H3K18la) modification, and this reduction subsequently downregulates the transcriptional expression of oncogenes, ultimately suppressing the growth of OC cells. This finding provides a novel mechanistic and experimental basis for the application of TCM-derived bioactive components in the metabolic-epigenetic combination therapy for OC. Mechanisms of histone lactylation regulating OC are summarized in Fig. 3.

Fig. 3.

Warburg effect-driven histone lactylation promotes chemoresistance, immune evasion, and tumor progression in ovarian cancer. In OC, enhanced glycolysis mediated by the Warburg effect promotes lactate production and accumulation, thereby inducing histone lactylation and regulating multiple molecular pathways associated with therapeutic resistance and immune escape

1. Mechanisms of chemoresistance: H3K18la can be enriched at the TRA2A promoter region and promote TRA2A transcription. TRA2A further mediates alternative splicing of STIL mRNA, increases the expression of the STIL-L isoform, and reduces cisplatin sensitivity by suppressing ferroptosis. H4K12la can act on the Nira-SE super-enhancer and promote high RAD23A expression through MYC-mediated transcriptional regulation, thereby enhancing DNA damage repair capacity and conferring niraparib resistance in OC cells. In addition, in platinum-resistant OC, H3K9la promotes the transcription of RAD51 and BRCA2, thereby enhancing homologous recombination repair. Meanwhile, RAD51 can also undergo non-histone lactylation at lysine 73 (RAD51K73la), further strengthening RAD51-mediated DNA repair function. Together, H3K9la and RAD51K73la promote HR repair and lead to platinum resistance.

2. Remodeling of the immune microenvironment: LDHB-mediated lactate production in OC cells can increase H3K18la levels at the PD-L1 promoter region, activate PD-L1 transcription, and suppress T-cell cytotoxic function, thereby promoting immune escape. FOXK1-mediated glycolipid metabolic reprogramming promotes lactate accumulation and induces CD8⁺ T-cell exhaustion by affecting TOX-associated lactylation levels and TOX expression in CD8⁺ T cells. In addition, lactate accumulated in the tumor microenvironment can be taken up by macrophages (blue cell) and induce their polarization toward the M2 phenotype (green cell). Meanwhile, lactate can activate CCL18 expression in macrophages through H3K18la, thereby promoting OC cell proliferation, migration, and tumor progression.

Cervical cancer

Cervical cancer (CC) is also one of the most common cancers in women. Although not the sole trigger, high-risk human papillomavirus infection is its primary causative factor [74]. As research into epigenetic modifications advances, the emerging histone lactylation modification has come to play a pivotal role in CC progression and gradually become a research focus. In 2019, researchers successfully identified 26 histone lactylation sites in HeLa cells—a finding that suggests histone lactylation may contribute to metabolism-related epigenetic regulation in this CC cell line [7]. With the continuous deepening of studies, the specific regulatory role of histone lactylation in CC has been gradually uncovered.

High concentrations of lactate in the TME have multiple pro-cancer effects. They participate in tumor cell metabolic reprogramming and promote tumor angiogenesis, metastasis and immune evasion through immunosuppressive effects [75]. This characteristic is particularly important during the progression from cervical intraepithelial neoplasia to CC, when the TME shifts from an ‘’immunologically activated’’ to an ‘’immunologically suppressed’’ state. Increased infiltration of M2 macrophages is a core feature of this transition. Huang et al. [76] demonstrated that, after lactate enters macrophages, it increases histone H3 lysine 18 lactylation (H3K18la) at specific loci within macrophages. H3K18la further activates the expression of the target gene GPD2. As a key downstream target gene, GPD2 mediates M2 macrophage polarization, ultimately driving the malignant transformation of CC. The study also showed that targeting GPD2 or inhibiting H3K18 lactylation reverses M2 macrophage polarization, providing a new approach to treating cervical precancerous lesions and CC clinically. Furthermore, T cells exhibit high sensitivity to extracellular lactate, influencing intracellular signaling, cellular function and overall homeostasis. Elevated lactate levels in the TME further impair T cell function and suppress immune responses [77]. Yang et al. [78] found that the expression levels of the key lactate metabolism–related genes lactate dehydrogenase A (LDHA) and SLC16A3 were significantly elevated in CC tissues. High lactate concentrations create an immunosuppressive microenvironment by reducing EP300-mediated histone lactylation, decreasing plasma cell-like dendritic cell infiltration and inhibiting central memory T cell activation. Inhibiting targets related to lactate production or transport using relevant inhibitors can reduce lactate secretion by CC cells and reverse immunosuppression. Notably, the distinct phenotypes of histone lactylation regulation observed in the above studies reflect the complexity and cell-type specificity of immune regulation within the TME. The regulatory effects of lactate on histone lactylation depend on differences in target cell types, modification sites, and downstream regulatory networks.

In CC, histone lactylation may not only function by reshaping the immune microenvironment but also exhibit site-specific competition and functional divergence with acetylation. Zhai et al. [43] found that lactate accumulation in CC cells markedly enhanced H3K14la rather than H3K14ac. In certain oncogenic gene regions, H3K14ac signals were substantially lower than H3K14la signals, suggesting that H3K14la may compete with acetylation at the same lysine residue and regulate transcription in a manner distinct from acetylation. This study further identified DPF2 as a reader of H3K14la and demonstrated that DPF2 recognizes the H3K14la mark and is enriched at the promoter regions of oncogenic genes, thereby driving gene transcription and tumor cell survival. These findings suggest that histone lactylation in CC does not function solely through a single linear pathway; rather, it can shape the immunosuppressive microenvironment and participate in transcriptional reprogramming through site-specific competition with acetylation and reader-mediated recognition mechanisms.

Endometrial cancer

Endometrial cancer (EC) is one of the common malignant tumors of the female reproductive system, and histone lactylation—an emerging epigenetic modification—has gradually gained attention for its role in driving EC progression. Wei et al. [79] found that, among five antibodies targeting histone lactylation sites (H3K181a, H3K271a, H3K141a, H3K91a, and H3K561a), H3K181a levels were most significantly elevated in EC tissues. H3K181a can bind to the promoter region of ubiquitin-specific protease 39 (USP39) and promote USP39 transcription. USP39, as a deubiquitinating-related protein, binds to phosphoenolpyruvate kinase 1 (PGK1) and stabilizes PGK1 through deubiquitination in a proteasome-dependent manner, thereby activating the PI3K/AKT/HIF-1α pathway, accelerating glycolysis, and promoting EC progression. Inhibiting histone deacetylase activity with 2-DG or targeting the USP39/PGK1 axis effectively suppresses EC progression.

Hypoxia is a core characteristic of the solid TME that participates in malignant tumor progression by inducing metabolic reprogramming of tumor cells and remodeling the immune microenvironment [80]. Sodium-hydrogen exchanger 7 (NHE7), a key member of the sodium-hydrogen exchanger family, maintains intracellular organelle pH homeostasis and ion balance [81]. It simultaneously serves as a pro-cancer hub within the hypoxic TME, and its expression status collectively drives EC progression through multiple pathways. Two studies from the same research group examined the pathogenic mechanisms of hypoxia in EC. These studies further confirmed the dual regulatory mode of NHE7. The first study revealed that EC cells induced by hypoxia generate substantial lactate through HIF1A-driven glycolysis [82]. Upon being taken up by macrophages, this lactate induces the modification of histone H3K18la. H3K18la then accumulates at the DNA methyltransferase 1 (DNMT1) promoter region, activating its transcription. DNMT1 then silences the NHE7 gene through DNA methylation, resulting in M2 macrophage polarization and senescence and ultimately promoting EC progression. The second study focused on the regulation of malignant phenotypes within the endothelial cells themselves. Hypoxia-driven glycolysis activates NHE7 transcription via histone lactylation (H3K18la) [83]. NHE7 then upregulates COX6C, which enhances OXPHOS and ROS production. This, in turn, induces endoplasmic reticulum stress. Ultimately, this promotes EC cell proliferation, migration, invasion, and stem cell-like properties. Mechanisms of histone lactylation regulating CC and EC are summarized in Fig. 4.

Fig. 4.

Pathological mechanisms of cervical and endometrial cancer driven by histone lactylation. Left panel: Cervical cancer (CC). In CC, enhanced glycolysis in CC cells promotes lactate production and accumulation. On the one hand, lactate accumulation increases H3K14la, which can be recognized by the reader DPF2. DPF2 and H3K14la are co-enriched at the promoter regions of target genes, activating the transcription of oncogenic genes such as SEMA5A and ROCK1, thereby promoting CC progression. On the other hand, CC cell-derived lactate can enter the tumor microenvironment and be taken up by macrophages, inducing increased H3K18la levels and activating GPD2 expression in macrophages, thereby promoting M2 macrophage polarization. In addition, lactate metabolism- and histone lactylation-related genes/regulators are associated with altered infiltration of immune cells, including plasmacytoid dendritic cells (pDCs) and central memory T cells (Tcm), as well as prognosis, suggesting that they may participate in the remodeling of the CC immune microenvironment. Right panel: Endometrial cancer (EC). In EC, hypoxia and enhanced glycolysis promote lactate accumulation and increased H3K18la levels. H3K18la can be enriched at the USP39 promoter region and promote USP39 transcription. USP39 further stabilizes PGK1 through deubiquitination, activates the PI3K/AKT/HIF-1α pathway, and enhances glycolysis, forming a “glycolysis–lactylation” positive feedback loop that promotes EC progression. Meanwhile, hypoxic glycolysis-driven H3K18la can activate NHE7 transcription. NHE7 further upregulates COX6C, enhances OXPHOS/ROS production, and induces endoplasmic reticulum stress, thereby promoting malignant EC progression. In addition, lactate derived from hypoxic EC cells can be transferred between tumor cells and macrophages and taken up by macrophages, inducing increased H3K18la levels at the DNMT1 promoter and activating DNMT1 transcription in macrophages. DNMT1 silences NHE7 through DNA methylation and activates MAPK-related signaling, thereby promoting macrophage senescence and M2 polarization, which collectively accelerate EC progression

Endometriosis

Recent studies indicate that histone lactylation is also extensively involved in the pathological processes of non-cancerous diseases [84, 85]. Although EMS is a benign disease, it exhibits biological behavior similar to that of malignant tumors: ectopic endometrial tissue achieves implantation metastasis via the blood or lymphatic circulation, with a recurrence rate of up to 50% [86]. Case reports also suggest that EMS may progress to OC [87, 88]. The chronic inflammatory state of EMS directly induces disruption to the local microenvironment, driving abnormal cell proliferation or lesion fibrosis [89]. Studies have revealed that elevated lactate levels are a hallmark not only of cancer, but also of multiple inflammatory diseases [90]. Lactate-induced histone lactylation may represent a key regulatory mechanism that drives disease progression and offers new perspectives on the research of EMS mechanisms and targeted interventions.

High mobility group protein 1 (HMGB1) is a multifunctional nuclear protein involved in cell proliferation, inflammatory responses and gene transcription. In tumors, it promotes invasion and metastasis by activating related pathways [91]. Chen et al. [92] found significantly elevated levels of lactate, LDHA, and H3K18la in endometriotic tissue and primary endometrial stromal cells. Lactic acid induces histone lactylation, which upregulates HMGB1 expression and activates the AKT pathway. This increases the expression of molecules related to proliferation, ultimately promoting the proliferation, migration, and invasion of ectopic endometrial cells. Inhibiting lactic acid production or targeting the HMGB1/AKT pathway reverses the malignant phenotype of ectopic endometrial cells.H19 is a long non-coding RNA (lncRNA) and a key member of the lncRNA family. Unlike protein-coding mRNA, H19 itself lacks the ability to encode proteins, but it participates in cellular physiological and pathological processes through various non-coding regulatory mechanisms [93]. Under pathological conditions, its expression often becomes abnormal, driving disease progression by regulating pathways such as metabolism, proliferation and invasion. Wen et al. [94] discovered significantly elevated H19 expression in both in situ and ectopic endometrial tissues within EMS, with higher levels observed in ectopic endometrium. H19 activates the aerobic glycolysis pathway, thereby increasing glucose consumption, lactate production and ATP synthesis in endometrial stromal cells, while also upregulating key glycolytic enzymes, including LDHA, PKM2 and ALDOA. Accumulated lactate acts as a substrate and elevates histone lactylation levels, with histone H3 lysine 18 lactylation (H3K18la) showing the most pronounced increase. This establishes a ‘’H19-aerobic glycolysis-lactate-histone lactylation’’ regulatory axis that promotes the proliferation and migration of endometrial stromal cells, thereby supporting the growth and invasion of ectopic endometrial tissue. In mouse models, inhibiting this regulatory axis with the glycolysis inhibitor 2-DG reduced ectopic lesion volume.

Notably, histone lactylation in EMS does not act solely through a single linear pathway but can form a cross-regulatory network with other post-translational modifications. The study by Wang et al. [58] provided relatively direct evidence for crosstalk between histone lactylation and other post-translational modifications in EMS. This study showed that H3K18la promotes ras-related dexamethasone-induced 2 (RASD2) transcription, and RASD2 further enhances cytidine triphosphate synthase 1(CTPS1) SUMOylation while suppressing its ubiquitination, thereby increasing CTPS1 protein stability and promoting EMs progression. In mouse models, inhibiting lactate production using 2-DG or Sodium Oxamate reduces H3K18la levels, downregulates the expression of RASD2 and CTPS1, and ultimately shrinks ectopic lesions. Liang et al. [95] further demonstrated that histone lactylation can undergo crosstalk with RNA m6A modification in EMS. This study showed that H3K18la promotes methyltransferase-like 3 (METTL3) expression and regulates the HIF1A/HMOX1 signaling axis through METTL3-mediated m6A modification, thereby enhancing ferroptosis resistance in ectopic endometrial stromal cells. This mechanism suggests that lactylation in EMS not only directly regulates target gene transcription but also further reshapes downstream post-transcriptional regulatory networks by influencing RNA m6A methylation. In mouse models, combined treatment with 2-DG and erastin reverses ferroptosis resistance, inhibits ectopic lesion growth, reduces M2 macrophage infiltration, promotes M1 macrophage polarization and improves the immunosuppressive microenvironment.

Polycystic ovary syndrome

PCOS, a prevalent endocrine metabolic disorder among women of reproductive age, involves a complex interplay of metabolic dysregulation, hormonal imbalance, and epigenetic regulation. Recent studies have revealed the specific mechanism by which histone lactylation mediates disease development from the perspectives of ovarian function regulation and endometrial receptivity.

Yu et al. [96] found that PKM2 expression was increased and accompanied by nuclear accumulation in ovarian granulosa cells from patients with PCOS. Nuclear PKM2 promotes nuclear lactate production, enhances histone lactylation modifications, including H3K9la, H3K18la, and H3K27la, and further induces three-dimensional genome architectural remodeling, including B-to-A compartment conversion, TAD fusion, and the formation of novel enhancer–promoter loops. This process upregulates androgen biosynthesis-related genes, including CYP17A1 and CYP11A1, as well as PCOS-related genes such as WNT4 and PADI3, which is closely associated with the development of hyperandrogenism. In animal models, treatment with TEPP-46, an inhibitor of PKM2 nuclear accumulation, blocked this regulatory axis and reversed the pathological phenotype. Another study revealed that impaired endometrial receptivity in PCOS patients is closely related to the abnormal elevation of ERα and histone lactate [97]. Clinical samples revealed that ERα, H3K18la, and H4K12la levels were significantly higher in the endometrium of women with PCOS, which was accompanied by the downregulation of the receptivity markers HOXA10 and COX2, as well as decidualization disorder.ERα mechanistically upregulates LDHA/LDHB, promoting lactate production.Lactate then induces H3K18la enrichment in the ESR1 promoter, enhancing its transcription and continuously activating the estrogen target gene LTF, as well as the endometrial receptivity-related genes MSX1 and MSX2. Ultimately, the polarity of the endometrial epithelium and the decidualization of stromal cells are impaired. Intrauterine injection of the ERα inhibitor MPP or the lactate production inhibitor sodium oxalate significantly reduced the levels of H3K18la and ERα and restored the embryo implantation rate.

Histone lactylation drives ovarian androgen synthesis by reshaping the three-dimensional genome. It also impairs endometrial receptivity through positive feedback loops with ERα. Thus, histone lactylation participates in core PCOS pathophysiological processes at multiple levels. These findings enrich the theoretical framework of metabolic-epigenetic cross-regulation in PCOS and provide crucial experimental evidence for precision therapeutic strategies targeting histone lactylation. Mechanisms of histone lactylation involved in the pathogenesis of EMS and PCOS are summarized in Fig. 5.

Fig. 5.

Histone lactylation drives the pathological mechanisms of endometriosis and polycystic ovary syndrome. Left panel: Endometriosis (EMs). In EMs, enhanced abnormal glycolysis promotes lactate accumulation and induces increased histone lactylation. Highly expressed lncRNA H19 upregulates glycolysis-related enzymes, including LDHA, PKM2, and ALDOA, thereby promoting lactate production and histone lactylation. Meanwhile, elevated H3K18la can be enriched at the HMGB1 promoter region and promote HMGB1 expression, further enhancing cell proliferation, migration, and invasion through AKT phosphorylation. H3K18la can also be enriched at the RASD2 promoter region and activate RASD2 transcription. RASD2 further enhances CTPS1 SUMOylation and inhibits its ubiquitination, thereby promoting EMs progression. In addition, H3K18la promotes METTL3 expression, enhances m6A modification, and regulates the HIF1A/HMOX1 signaling axis, thereby mediating ferroptosis resistance in ectopic endometrial cells. Right panel: Polycystic ovary syndrome (PCOS). In PCOS, PKM2 expression is increased and accompanied by nuclear accumulation in ovarian granulosa cells. Nuclear PKM2 promotes nuclear lactate production, enhances histone lactylation modifications, including H3K9la, H3K18la, and H3K27la, and induces three-dimensional genome architectural remodeling. These changes further upregulate the expression of androgen biosynthesis-related genes, including CYP17A1 and CYP11A1, as well as PCOS-related genes such as WNT4 and PADI3, thereby promoting the development of hyperandrogenism. On the other hand, in the PCOS endometrium, increased ERα promotes LDHA and LDHB expression, enhances lactate production, and induces increased H3K18la at the ESR1 promoter region. H3K18la further activates ESR1/ERα expression, forming an ERα–LDHA/LDHB–lactate–H3K18la–ESR1/ERα positive feedback loop, and promotes the transcription of estrogen-responsive genes such as LTF, MSX1, and MSX2. Ultimately, this process leads to decreased decidualization- and implantation-related markers, including IGFBP1, PRL, COX2, and HOXA10, resulting in impaired endometrial receptivity

Common and specific features of gynecological benign and malignant diseases mediated by histone lactylation

As a key modification linking metabolic reprogramming and epigenetic regulation, histone lactylation plays a crucial regulatory role in various gynecological diseases, including OC, CC, EC, EMS and PCOS. Comparative analysis of the molecular mechanisms underlying these diseases reveals that regulatory patterns of histone lactylation exhibit highly conserved commonalities, as well as significant disease-specific characteristics. These collectively shape the differential regulatory landscape of histone lactylation in gynecological diseases.

From a common-mechanisms perspective, histone lactylation exhibits highly consistent regulatory patterns across various gynecological diseases. Histone lactylation is a pivotal node in the cross-regulation of metabolism and epigenetics in benign and malignant gynecological diseases. It drives disease progression by mediating biological processes such as cellular metabolic reprogramming, immune microenvironment remodeling, and cell proliferation/migration, and it exhibits distinct common regulatory characteristics. First, H3K18la is the primary histone lactylation site at the center of all gynecological diseases. It is the primary regulatory target in OC, CC, EC, EMS, and PCOS. Therefore, H3K18la can be used as a general epigenetic research target for these diseases. Second, reshaping the immunosuppressive microenvironment is a common pathogenic mechanism of histone lactylation; by inducing M2 polarization of macrophages and suppressing the function of effector T cells, it contributes to disease progression in malignant conditions such as OC, CC, and EC. Third, histone lactylation forms a crosstalk network with other PTMs instead of acting independently. For instance, in CC, H3K14la and H3K14ac achieve the selective regulation of transcription of downstream oncogenes by sharing chromatin binding sites and competing for the binding preference of regulatory proteins [43]. In EC, H3K18la indirectly regulates PGK1 ubiquitination by activating USP39 [79] and enriches in the DNMT1 promoter to activate transcription and silence the NHE7 gene through DNA methylation [82]. In EMS, lactylation engages in competitive crosstalk with SUMOylation [58] and acts synergistically with m6A modification to mediate ferroptosis resistance in lesion cells [95]. These findings indicate that histone lactylation is not an isolated epigenetic modification in gynecological diseases. Instead, it participates in multilayered regulatory networks involving SUMOylation, ubiquitination, DNA methylation, and RNA m6A modification, thereby enabling cross-modification signal transmission and contributing to disease progression. Notably, in the TME, such crosstalk is not confined to tumor cells themselves but often begins with intercellular lactate transfer. Lactate released by tumor cells can be taken up by macrophages or T cells, inducing increased levels of lactylation marks such as H3K18la and H3K14la in immune cells. These changes may further reshape the immunosuppressive microenvironment through DNA methylation, immune checkpoint regulation, or cytokine expression.

By contrast, histone lactylation exhibits distinct specificity to various gynecological conditions, which is crucial for its ability to mediate different phenotypes. Firstly, lactylation sites exhibit disease specificity. For instance, H3K14la is predominantly found in CC and has a carcinogenic effect; however, its presence in other gynecological diseases is rare. Second, the functional pathways exhibit disease specificity. While both EMS and OC exhibit lactylation-related ferroptosis resistance, the former relies on the METTL3-HIF1A/HMOX1 pathway and the latter on TRA2A-mediated alternative splicing. This indicates that different diseases have distinct mechanisms. Meanwhile, multiple lactylation sites (H3K18la, H3K9la, and H4K12la) in OC are involved in regulating therapeutic resistance, representing one of the most prevalent lactylation-driven resistance mechanisms in malignant tumors. Third, downstream effectors are disease-specific. The core downstream target genes regulated by lactylation differ significantly among diseases. For instance, RAD51 and BRCA2 are highly associated with OC, GPD2 and DPF2 with CC, USP39 and NHE7 with EC, HMGB1 and METTL3 with EMS, and MSX1 with PCOS.

In summary, histone lactylation exhibits common core regulatory features as well as disease-specific patterns in the progression of gynecological diseases. Conserved lactylation sites, along with common epigenetic modifications, establish the fundamental regulatory framework. Meanwhile, disease-specific site preferences, signaling pathway selection, and downstream target gene profiles shape the unique pathological phenotypes of different gynecological diseases. It is worth noting that the common and specific roles of histone lactylation in benign and malignant gynecological diseases summarized above are based on currently published studies. As research on the relationship between histone lactylation and gynecological diseases progresses, the relevant evidence will continue to grow, and the potential regulatory rules and disease-specific mechanisms will be further explored. Therefore, histone lactylation may be significant in diagnosing and treating diseases, potentially becoming a therapeutic target in the future.

Potential therapeutic strategies

Targeting lactic acid metabolism

Lactic acid is the direct substrate for histone lactylation. In tumors and metabolic diseases, lactic acid accumulation is the main cause of increased histone lactylation. Inhibiting lactic acid production or transport can indirectly reduce histone lactylation levels. Current studies usually suppress lactic acid production by targeting lactate dehydrogenase or other glycolytic enzymes. LDHA and LDHB are pivotal enzymes in glycolysis, acting as reversible catalysts for the conversion between pyruvate and lactate and directly influencing lactate accumulation and lactate modification [98]. LDHA inhibitors suppress tumor metabolic reprogramming and immune evasion by reducing lactate production and lowering histone lactylation levels [99]. Li et al. [100] found that treatment with the LDHA inhibitor Oxamate, or LDHA gene knockdown, effectively reduced H3K18la levels in pancreatic ductal adenocarcinoma (PDAC) tumor cells, significantly inhibiting their proliferation and migration capacity. Meanwhile, research has revealed an intriguing phenomenon: the function of LDH isoforms is not absolute, but rather highly dependent on the metabolic environment of the cell. While LDHB is classically recognized for its role in converting lactate to pyruvate, Zhang et al. [101]observed its expression to be synchronously elevated with histone H3K18 lactylation in osteoarthritis studies. The administration of LDHB inhibitors, or Oxamate, has been demonstrated to alleviate disease progression. This finding indicates that LDHB may play a regulatory role in disease progression through the process of lactylation in specific pathological contexts, thus rendering LDHB targeting a potential therapeutic strategy. Another promising approach involves the use of 2-DG. Hexokinase (HK), the first key enzyme in glycolysis, catalyses the phosphorylation of glucose to glucose-6-phosphate, thereby initiating glycolysis [102]. As an HK inhibitor, 2-DG competitively inhibits HK activity, blocking glucose phosphorylation and thereby suppressing glycolysis and reducing lactate production [103]. Fang et al. [104] provided robust in vivo evidence supporting this strategy. They demonstrated that 2-DG intervention in a mouse model of spontaneous atrial fibrillation effectively suppressed atrial glycolysis and lactate production, ultimately significantly reducing susceptibility to and duration of fibrillation. The underlying mechanism involves 2-DG reducing lactate, a key signaling molecule, thereby inhibiting histone H3K18 lactylation (H3K18la)—an epigenetic modification that promotes fibrosis—and blocking cardiac fibroblast activation and atrial fibrosis progression. Additionally, pyruvate kinase (PK) is one of the key rate-limiting enzymes in glycolysis and a significant potential target for glycolysis-directed therapies [105]. Its core isoform, PKM2, is highly expressed in various tumor cells, supporting rapid tumor proliferation by regulating glycolytic flux. This makes PKM2 a current hotspot in cancer treatment research [106]. Similarly, PKM2 can serve as a therapeutic target in intestinal ischemia-reperfusion injury. Liu et al. [107] found that PKM2 expression increased significantly in an intestinal ischemia-reperfusion model. This promoted the modification of histone H4K12 by lactate via the lactic acid/p300 axis, thereby activating HMGB1 transcription and ultimately inducing ferroptosis in intestinal epithelial cells and exacerbating tissue damage. However, the PKM2 dimer inhibitor ML265 effectively blocked this pathway and alleviated intestinal injury. Notably, the potential of natural compounds to inhibit lactate production is an area of increasing exploration. Studies reveal that excessive PKM2-induced lactate generation in renal tubular cells promotes histone lactylation, ultimately driving renal fibrosis [108]. Treatment with the natural compound pallidol effectively blocks this pathological cascade by targeting PKM2 activity, thereby controlling renal fibrosis in chronic kidney disease.

The monocarboxylate transporter (MCT) family constitutes the core proteins that facilitate the movement of lactate across cell membranes. MCT1 and MCT4 are pivotal members of this family, regulating lactate transport and playing an irreplaceable role in maintaining the glycolysis-dependent metabolic phenotype of cancer cells [109]. The targeting of these transporters has been demonstrated to disrupt lactate efflux, leading to intracellular lactate accumulation and subsequent metabolic stress [110]. Zhang et al. [111] demonstrated that inhibition of MCT4 in macrophages increases the level of histone H3 lysine 18 lactylation (H3K18la). This elevation activates the expression of reparative genes, promotes the polarization of macrophages toward the M2 reparative phenotype, and thereby alleviates atherosclerosis. In addition to MCT4, studies have shown that blocking MCT1 with AZD3965 inhibits lipid biosynthesis and enhances the infiltration of tumor-infiltrating immune cells [112]. However, traditional MCT1 inhibitors such as AZD3965 block MCT1’s lactate transport function, yet they cannot interfere with its interactions with key accessory proteins [113]. CD147 stabilizes MCT1’s localization to the cell membrane, ensuring the normal mediation of tumor cell lactate secretion and immune cell lactate uptake. The integrity of this complex is crucial for establishing a high lactate state and immune suppression within the TME [114, 115]. Recent melanoma studies reveal that crizotinib binds directly to CD147 and MCT1, disrupting their formation of a complex to block lactate transport at its source [116]. This reduces lactate secretion by melanoma cells while inhibiting lactate uptake by macrophages. It was found to lower H3K18la levels in macrophages, reverse M2 polarization, enhance CD8 + T cell function and ultimately suppress melanoma growth, invasion and immune evasion. This study demonstrates that crizotinib has a unique regulatory mechanism that is distinct from that of conventional MCT1 inhibitors. In summary, the strategic inhibition of lactate production and transport represents a novel and promising therapeutic approach involving the modulation of lactate metabolism.

Enzymes that target histone lactylation modification

Enzymes that are targeted for lactylation modification include both the “writers” of lactylation and potential “erasers”. The development of specific small-molecule inhibitors represents a promising approach for targeting the enzymes involved in catalyzing histone lactylation in the context of histone lactylation “writers”. These inhibitors function by impeding the transfer of lactyl groups to specific histone sites, thereby aiming to reduce abnormal lactylation levels at the source. Liu et al. [117] revealed that the transcription factor CCCTC-binding factor (CTCF) promotes histone lactylation in PDAC by recruiting p300, thereby driving tumor-associated macrophages toward M2 polarization to remodel the immunosuppressive microenvironment and accelerate tumor progression. The combination of the CTCF inhibitor Curaxin and gemcitabine has been shown to be significantly efficacious in the treatment of PDAC [117]. Research indicates that lactylation also influences malignant phenotypes and therapeutic resistance by regulating key biological processes in tumour stem cells, including stemness maintenance, self-renewal, and differentiation capacity [6]. The targeting of p300 or LDHA has been shown to reduce H4K12la levels, thereby deactivating lactylation-mediated activation of chemotherapy resistance genes and enhancing chemotherapy sensitivity in colorectal cancer (CRC) stem cells [118].

HDAC1-3 and SIRT1-3 have been identified as effective mediators of histone lactylation removal and participate in key steps of lactylation-mediated gene regulation [36, 119]. Numerous preclinical studies have demonstrated that designing corresponding agonists can reverse the buildup of excessive lactate by enhancing their “eraser” function on modified lactate groups. Li et al. [120]discovered that TRAP1 promotes vascular smooth muscle cell senescence and atherosclerosis by increasing levels of H4K12 lactylation (H4K12la) through the downregulation of HDAC3 activity. Treatment with the HDAC activator ITSA-1 reduces H4K12la levels by activating HDAC3, thereby blocking these pathological processes. Regarding the SIRT family, a combination of the SIRT1 activator SRT2104 and the LDHA inhibitor Oxamate inhibited the proliferation of gastric cancer cells [38]. This dual-targeted therapeutic approach combines lactate pathway inhibition with targeted therapy to enhance treatment efficacy. Effective suppression of disease progression can be achieved by targeting “writers” to inhibit histone lactylation or by regulating “erasers.”

Combined therapy strategies

Given that lactylation regulation involves a multi-step cascade reaction encompassing “lactate metabolic production—lactylation modification catalysis—downstream pathological effect activation”, single-target intervention often fails to completely block disease progression due to pathological compensatory mechanisms or limited action scope. Therefore, combination therapy based on lactylation regulation represents a crucial direction for future cancer treatment. By synergizing with existing immunotherapy, radiotherapy, and chemotherapy regimens, it can overcome the efficacy bottleneck of single-agent therapy and serve as a key approach to improve therapeutic outcomes. A substantial body of research has demonstrated the feasibility and superiority of the proposed approach. In non-small cell lung cancer, the combined use of glycolysis inhibitors and anti-PD-1 antibodies induces the function of intratumoral CD8 + T cells and exhibits potent anti-tumor efficacy [121]. This finding indicates that metabolic reprogramming and immunotherapy can be used to reverse immune suppression. Li et al. [122] combined strategies targeting lactate production with bevacizumab administration. This combination significantly reduced the levels of H3K18la and RUBCNL, blocked autophagosome maturation, and exhibited more potent tumor growth inhibition compared to bevacizumab monotherapy. Combining this approach with the autophagy inhibitor chloroquine further enhanced CRC sensitivity to bevacizumab. Additionally, Zhao et al. [123] suppressed melanoma progression by combining LDHA inhibitors with anti-angiogenic strategies.

In summary, emerging therapeutic strategies targeting lactylation—such as inhibiting lactate production (LDHA/LDHB), lactate transport (MCT1/4), histone lactylation-related enzymes (p300/SIRT), or downstream effectors—exhibit the potential to reshape the TME, enhance the efficacy of immune checkpoint blockade therapy, and overcome drug resistance. As also summarized in the preceding sections, in the field of gynecological diseases, intervention strategies targeting lactate generation (e.g., 2-DG-mediated glycolysis inhibition) [70], lactate transport (e.g., targeting MCT1) [76], lactate-modifying enzymes (e.g., MB-3 targeting GCN5) [68], or downstream signaling pathways (e.g., targeting the USP39/PGK1 axis) [79] have demonstrated efficacy in inhibiting disease progression in certain experimental models of gynecological disease (Table 2). Similar regulatory logic is reflected in the above-mentioned studies of metabolic diseases, cardiovascular diseases, and other fields, in addition to gynecological diseases. This suggests that histone lactylation may serve as a common potential therapeutic target across different disease types. Furthermore, further elucidation of its tissue- and cell-specific regulatory mechanisms will provide stronger theoretical support and practical directions for the precise diagnosis and treatment of gynecological diseases.

Table 2.

Summary of histone lactylation-mediated mechanisms and targeted inhibitors in gynecological diseases

Disease	Histone Lactylation Sites	Genes affected by histone lactylation	Positive/negative regulation	Biological Effects	Inhibitor name	Targets	Effects	Refs.
OC	H3K18la	/	+	Enhancing OC cell migration capacity and platinum resistance	Oxamate	Oxamate: targeting LDH	In vitro: Cell migration capacity was significantly reduced compared to the L-lactic acid-treated group	[60]
OC	H3K18la	CCL18	+	Inducing Macrophage M2 Polarization, Enhance OC cell proliferation and migration, Promoting tumor growth and liver metastasis	1. Gpr132 siRNA 2. Anti-CCL18 antibody 3.Oxamate	1. Gpr132 siRNA: targeting Gpr132 2. Anti-CCL18 antibody: targeting CCL18 3. Oxamate: targeting LDH	In vitro: Inhibit macrophage polarization toward the M2 type, Decreased proliferation and migration capacity of OC cells In vivo: Nude mice exhibited significantly reduced tumor volumes and a marked decrease in the number of liver metastases	[61]
OC	H3K18la	PD-L1	+	Inhibition of T-cell Function, Promote immune escape	1. LDHB siRNA 2. AXKO-0046 3. Anti-PD-L1 antibody	1. LDHB siRNA、AXKO-0046: targeting LDHB 2. Anti-PD-L1 antibody: targeting PD-L1	In vitro: Restoring the antitumor immune function of T cells	[63]
OC	H3K9la	RAD51、BRCA2	+	Enhanced HR Repair, Mediated platinum resistance, Associated with poor prognosis	1.2-DG 2.FX-11 3.MB-3	1. 2-DG: targeting GLUT、HK 2. FX-11: targeting LDH 3. MB-3: targeting GCN5	In vitro: Reversing Platinum Resistance in OC	[68]
OC	H4K12la	RAD23A	+	Enhanced DNA damage repair, Mediated Niraparib Resistance	1. 2-DG 2. PKM siRNA/LDHA siRNA 3. RAD23A siRNA	1. 2-DG: targeting GLUT、HK 2. PKM siRNA/LDHA siRNA: targeting PKM、LDHA 3. RAD23A siRNA: targeting RAD23A	In vitro: Restoring sensitivity to niraparib in drug-resistant cells In vivo: Reduce tumor volume and inhibit organoid growth	[70]
OC	H3K18la	TTK、PDGFRβ、YTHDF2、RUBCNL	-	/	Tanshinone I	1. Direct target: FOXK1/2 2. Indirect targets: HK2、PFK、LDHA	In vitro: Reduce OC cell proliferation、Induce its death、Improve the immune microenvironment In vivo: Nude mice exhibited a significant reduction in tumor volume and weight	[73]
OC	Pan-lactylation	TOX	+	Promote CD8⁺ T cell exhaustion, inducing tumor immune escape	1. FOXK1 siRNA/shRNA 2. 2-DG 3. Oxamate	1. FOXK1 siRNA/shRNA: targeting FOXK1 2. 2-DG: targeting HK 3. Oxamate targeting LDHA	In vitro: Inhibits tumor cell proliferation and migration, improves the immune microenvironment In vivo: Reduces tumor volume	[64]
OC	H3K18la	TRA2A、STIL	+	Suppression of ferroptosis, enhanced survival capacity of OC cells, and reduced sensitivity to cisplatin treatment	1. TRA2A siRNA/shRNA 2. DDP	1. TRA2A siRNA/shRNA: targeting TRA2A; 2. DDP: targeting DNA	In vitro: Restores cancer cells’ sensitivity to cisplatin In vivo: Significantly inhibits tumor growth	[71]
CC	H3K18la	GPD2	+	Promote immunosuppression、Accelerate malignant transformation	1.Oxamate 2.SR13800 3.GPD2 siRNA	1.Oxamate: targeting LDH 2.SR13800: targeting MCT1 3. GPD2 siRNA: targeting GPD2	In vitro: Inhibit macrophage polarization toward the M2 type	[76]
CC	Not mentioned	1. Lactate metabolism genes: LDHA、SLC16A3/MCT4 2. Histone lactylation-related genes: EP300、ACAT1、ACACA	+、-	Promote immunosuppression	1.Oxamate 2.SLC16A3 inhibitor	1.Oxamate: targeting LDHA 2. SLC16A3 inhibitor: targeting SLC16A3	In vitro: Restore CD8⁺ T cell cytotoxic function、Reversal of Immunosuppression	[78]
CC	H3K14la	1.Oncogenes: SEMA5A、ROCK1、SOAT1 2. Regulatory factors: DPF2	+	Enhance the proliferative capacity of CC cells	Sodium Oxamate	Sodium Oxamate: targeting LDH	In vitro: CC cell proliferation capacity is significantly reduced	[43]
EC	H3K18la	USP39	+	Activate the PI3K/AKT/HIF-1α signaling pathway, Promote USP39 gene expression, Promote tumor progression	1.2-DG 2. Oxamate	1. 2-DG: targeting GLUT、HK 2.Oxamate: targeting LDH	In vitro: Reduced cell proliferation and migration capacity In vivo: The tumor volume and weight in nude mice were significantly reduced	[79]
EC	H3K18la	DNMT1、NHE7、MCT1、MCT3	+	Promote macrophage M2 polarization and senescence, accelerating EC progression	1. OA 2. 5-aza 3. U0126	1. OA: targeting LDH 2. 5-aza: targeting DNMT1 3. U0126: targeting MAPK	In vitro: Inhibits M2 polarization and senescence of macrophages In vivo: Reduces tumor volume	[82]
EC	H3K18la	NHE7、COX6C、HK2、GLUT4、LDHA	+	Enhances OXPHOS activity, ROS accumulation, induces endoplasmic reticulum stress, and promotes EC malignant phenotype	1. 2-DG 2.Sodium Oxamate 3. 4-PBA 4. Ceapin-A7 5. NHE7 siRNA/shRNA 6. COX6C siRNA; 7. NAC	1. 2-DG: targeting HK 2. Sodium Oxamate: targeting LDHA 3. 4-PBA/Ceapin-A7: targeting endoplasmic reticulum stress pathway; 4. NHE7 siRNA/shRNA: targeting NHE7 5. COX6C siRNA: targeting COX6C 6. NAC: targeting ROS	In vitro: Inhibits OXPHOS and ROS production, alleviates endoplasmic reticulum stress; attenuates malignant phenotype of EC cells In vivo: Reduces volume and weight of EC xenograft tumors	[83]
EMS	H3K18la	HMGB1	+	Activate the AKT pathway, Promote the proliferation of ectopic endometrial cells、Migration and Invasion	1.2-DG 2. HMGB1 siRNA	1. 2-DG: targeting HK 2. HMGB1 siRNA: targeting HMGB1	In vitro: Reversing the malignant phenotype of ectopic endometrial cells	[92]
EMS	H3K18la	H19	+	Enhance the invasive capacity of ectopic endometrial cells, Promote lesion growth	1.2-DG 2.H19 siRNA	1. 2-DG: targeting HK 2.H19 siRNA: targeting H19	In vitro: Reduced proliferation and migration capacity of ectopic endometrial cells In vivo: Reduce ectopic lesions	[94]
EMS	H3K18la	RASD2、CTPS1	+	Enhance the invasive capacity of ectopic endometrial tissue, Promote lesion growth	1.2-DG 2. Sodium Oxamate	1. 2-DG: targeting HK 2. Sodium Oxamate: targeting LDHA	In vitro: Reduced proliferation, migration, and invasion capabilities of ectopic endometrial cells In vivo: Reduce ectopic lesions	[58]
EMS	H3K18la	METTL3	+	Promoting ferroptosis resistance、promote M2 macrophage infiltration, Suppression of antitumor immunity	1. 2-DG 2.erastin; 3. METTL3 siRNA	1. 2-DG: targeting HK 2.erastin: targeting System xc⁻ 3. METTL3 siRNA: targeting METTL3	In vitro: Endometrial cell proliferation in ectopic locations、Decreased mobility、Reversing Iron Death Drug Resistance In vivo: Reduce ectopic lesions、Reversing immunosuppression	[95]
PCOS	H3K9la、H3K18la	PKM2、CYP17A1、CYP11A1、CPZ、PADI3	+	Causes hyperandrogenism, ovulatory dysfunction, and PCOS-like phenotypes, leading to reduced fertility	1. TEPP-46 2. 2-DG 3. Sodium Oxamate	1. TEPP-46: targeting PKM2 2. 2-DG: targeting HK 3. Sodium Oxamate: targeting LDHA	In vitro: Reduces expression of H3K9/18la and PCOS-associated genes In vivo: Restores estrous cycles and fertility in mice, improves polycystic ovarian changes	[96]
PCOS	H3K9la、H3K18la	ESR1(ERα)、MSX1、MSX2、LTF	+	Leading to impaired endometrial receptivity and abnormal epithelial hyperplasia	1. MPP 2. Sodium Oxamate 3. ERα siRNA	1. MPP: targeting ERα 2. Sodium Oxamate: targeting LDHA 3. ERα siRNA: targeting ESR1	In vitro: Sodium oxalate reduces H3K18la and ERα expression In vivo: Restores the number of implantation sites and improves endometrial receptivity	[97]

Feasibility and challenges of clinical translation and application

Although histone lactylation production shows great theoretical potential as a therapeutic target and biomarker, transforming it from preclinical research to clinical application faces severe challenges. These challenges focus on the following five aspects.

Insufficient target specificity and off-target effects

The most commonly used interventions that target lactate production, such as 2-DG and sodium oxalate, are all non-specific metabolic inhibitors. For instance, 2-DG reduces lactate production by blocking glucose glycolysis. While 2-DG successfully inhibits histone lactylation, it also interferes with the basal glucose metabolism of normal tissues, leading to systemic toxicity and off-target risks [124, 125]. Similarly, targeting lactate transport faces comparable challenges. The phase I clinical trial of AZD3965, conducted by Halford et al. [126], reported asymptomatic, reversible electroretinogram changes and grade 3 acidosis in patients. These dose-limiting toxicities were directly related to the physiological expression of MCT1 in the retina and heart. Histone lactylation shares “writers” and “erasers” with other histone modifications, which makes regulating it specifically exceptionally challenging. For example, many studies have reduced histone lactylation levels by silencing EP300, which has also lowered overall acetylation levels. Directly targeting this enzyme could lead to unintended epigenetic disruption and increase off-target risks [50]. Furthermore, the molecular mechanisms underlying the “cross-talk” between histone lactylation and other epigenetic modifications have yet to be systematically elucidated. Without a precise molecular foundation, drug design targeting lactylation is at risk of off-target effects. Therefore, it is critically important to identify novel approaches to specifically regulate overall lactylation levels.

Cellular heterogeneity in the tumor microenvironment and delivery challenges

The TME is well-known to be composed of diverse and complex elements, including tumor cells, immune cells, stromal cells, and other cellular components. This environment exhibits high cellular heterogeneity and presents significant barriers to drug delivery. If drugs act indiscriminately on all cells, they may suppress tumor growth while simultaneously weakening the body’s antitumor immune response, thereby negating therapeutic efficacy. For instance, lactylation of the same site (H3K18la) promotes immune evasion in OC cells by activating PD-L1 [63]. However, H3K18la mediates M2 polarization in tumor-associated macrophages [61]. This functional heterogeneity directly impacts the specificity of H3K18la as a therapeutic target. Indiscriminate targeting could disrupt normal immune cell function and cause treatment-related side effects. Therefore, developing cell-selective delivery strategies is crucial for precise intervention. In the field of emerging nanotechnology, drugs such as lactate inhibitors and immunotherapy drugs are delivered synchronously, accurately, and systematically to tumor tissues through different mechanisms, improving the targeting and effectiveness of drug action. Active targeting through antibody modification [127], stimulus-responsive nano platform design using TME characteristics [128], and strategies to enhance drug retention through local injection combined with nanocapsules [129]have shown great potential in selectively enriching drugs in tumor tissues and enhancing anti-tumor immune efficacy.

Activation of metabolic compensatory pathways and therapeutic escape

Tumor cells exhibit remarkable metabolic plasticity. Studies indicate that, when the glycolytic pathway is blocked by drugs, some tumor cells can rapidly activate compensatory mechanisms. They restore lactate levels by enhancing glutamine catabolism to produce lactate, which leads to drug tolerance or tumor progression [130]. Additionally, targeting key enzymes in the glycolytic pathway activates alternative enzymes, enabling cells to bypass the blocked pathway. For example, in pancreatic cancer models, treatment with LDHA inhibitors resulted in significant upregulation of LDHB in resistant cells to sustain lactate metabolism [131]. In addition to metabolic changes, tumors “compensate” for functional deficits caused by the inhibition of lactate production by activating other signaling pathways. Studies have confirmed that LDHA inhibition activates either the AMPK-mTOR-S6K signaling pathway [132]or the mTORC1 signaling pathway [133]. Therefore, targeted therapies against lactate production must also consider inhibiting these compensatory signaling pathways. Although targeted lactylation is believed to reverse T cell exhaustion and M2 macrophage polarization, studies indicate that inhibiting lactylation alone frequently activates compensatory mechanisms in tumor cells. This compensation primarily manifests as abnormal PD-L1 overexpression and increased immunosuppressive cell infiltration. Ultimately, this exacerbates immune escape rather than achieving the anticipated immune restoration. A clinical study confirmed that the -SG diet inhibits tumor cell proliferation and recruits CD8 + T cell infiltration by restricting the intake of exogenous serine and glycine [134]. However, it simultaneously induces tumor cells to initiate compensatory glycolysis, which leads to increased endogenous lactate production [134]. Elevated lactate, which is catalyzed by GCN5, promotes the lactylation modification of PD-L1 [134]. This enables PD-L1 to evade lysosomal degradation and enhances its stability as a protein [134]. Consequently, PD-L1 is highly expressed on the tumor cell surface, which counteracts the antitumor effects of T cells [134]. Therefore, to overcome this compensatory barrier, targeting lactylation must be combined with immune checkpoint inhibitors.

Specific translational barriers in benign and malignant gynecological diseases

Gynecological diseases have distinct anatomical structures and pathological characteristics that present unique challenges for clinical translation. OC is primarily characterized by peritoneal dissemination, which requires drugs to penetrate the complex peritoneal microenvironment and reach micrometastases scattered across the peritoneal surface. EMS are diffusely distributed throughout the pelvis and are influenced by estrogen fluctuations during the menstrual cycle. Improper timing of intervention may result in inconsistent efficacy. CC is localized to the cervix, where the local microbial ecosystem and mucus barrier can affect the stability and delivery efficiency of drugs. PCOS is a complex condition involving systemic metabolic disorders and local ovarian regulation. Correcting systemic abnormalities, such as insulin resistance, by simply targeting local ovarian lactate is difficult. PCOS patients are primarily women of childbearing age, so targeted drugs must undergo rigorous reproductive toxicity evaluations to avoid interfering with follicular development, embryo implantation, and other physiological processes. These anatomical, hormonal, and metabolic particularities necessitate the development of differentiated delivery strategies and intervention programs for various gynecological diseases.

Potential and challenges of using histone lactylation as a biomarker

The detection of histone lactylation can compensate for the shortcomings of traditional lactate, which only reflects metabolic levels and does not reflect functional effects. Additionally, it can serve as a functional marker to characterize pathological processes related to lactic acid. This potential has been well demonstrated in multiple disease classes. In addition to the aforementioned findings regarding gynecological diseases, H3K18la levels in pancreatic and colorectal cancer tissues are closely related to patient prognosis [135, 136]. Furthermore, histone lactylation modification has been found to participate in the pathological process and show the potential of birth markers in non-tumor diseases such as sepsis [137], cardiovascular and cerebrovascular diseases [85], sepsis-related acute respiratory distress syndrome [138], and neurodegenerative diseases [139].

Despite the broad potential of histone lactylation as a biomarker, limitations in basic research currently hinder its clinical translation and application. First, the disease specificity of different histone lactylation sites (e.g., H3K18la and H4K12la) is unclear, which makes developing site-specific biomarkers difficult. Second, the differences in histone lactylation expression among different disease subtypes (e.g., serous versus clear-cell OC) remain unclear. This complicates subtype-specific diagnosis and stratification. Additionally, there is extensive crosstalk between histone lactylation and other PTMs, which makes distinguishing its independent pathological significance difficult when only histone lactylation is detected. Third, the role of non-histone lactylation remains unclear. Although multi-focus histone lactylation has been studied, a large number of non-histone lactylation modifications exist in various diseases, including gynecological diseases. These modifications are also involved in pathological processes, and their synergistic or antagonistic effects with histone lactylation are unclear. This complicates the interpretation of histone lactylation as a marker.

Beyond the bottlenecks in fundamental research, technical gaps further restrict the use of histone lactylation as a specific biomarker. Currently, detection strategies for histone lactylation have evolved into a multi-tiered technical framework. Western blotting is a simple, inexpensive technique that enables rapid, semi-quantitative detection of site-specific lactylation modifications. It is suitable for the initial screening of large volumes of clinical samples [100]. Through antibody labeling and fluorescent staining, immunohistochemistry and immunofluorescence allow for the direct visualization of histone lactylation localization and distribution in cells or tissues, providing morphological evidence for mechanistic studies [100, 140]. Chromatin immunoprecipitation (ChIP-qPCR and ChIP-seq) can accurately determine histone lactylation levels at specific gene promoters and functional regions [141, 142]. CUT&Tag is an improved chromatin-binding technique that uses its high sensitivity to efficiently detect lactylation modifications [55]. This makes CUT&Tag particularly suitable for samples with low cell numbers or clinical trace samples. Liquid biopsy represents a more promising application direction, including the detection of histone lactylation in circulating nucleosomes released into the bloodstream or in tumor-derived exosomes [143]. For circulating nucleosomes, cell-free nucleosomes or cell-free chromatin can first be enriched from plasma or serum. Immunocapture can then be performed using anti-H3, anti-nucleosome, or site-specific lactylation antibodies, followed by ELISA, cfChIP-seq, or related approaches to detect potential lactylation biomarkers [144, 145]. For tumor-derived exosomes, exosomes can be enriched by ultracentrifugation, size-exclusion chromatography, or immunoaffinity capture, and their origin can be characterized using CD63, CD81, TSG101, and tumor-associated markers. Histones or histone lactylation signals carried by these exosomes can then be detected [146, 147]. Finally, mass spectrometry, owing to its high resolution and antibody-independent nature, can accurately identify and quantify histone lactylation modifications. This approach is particularly suitable for discovering novel biomarker sites or serving as a validation method [148].

However, current detection systems still exhibit obvious limitations. On the one hand, most available antibodies are polyclonal, which are prone to cross-reactivity with structurally similar short-chain acyl modifications such as acetylation and propionylation. Due to insufficient specificity, it is difficult to accurately distinguish signals from individual lactylation sites [149]. At the same time, methods such as immunofluorescence based on fixed samples have difficulty achieving real-time dynamic tracking of lactylation modifications in live cells. Additionally, although liquid biopsy shows great clinical promise, it faces challenges such as low levels of circulating targets, short half-lives, and complex sources, which make tumor-specific signals susceptible to interference [150]. In addition, techniques such as ChIP and CUT&Tag still demand relatively high input cell numbers or sample quality, and their experimental procedures and bioinformatic analysis pipelines have not been standardized. Although mass spectrometry offers high accuracy, its high instrumental cost and cumbersome sample preparation restrict its widespread application as a routine clinical detection method.Therefore, there is an urgent need to develop highly specific antibodies, efficient enrichment methods, and standardized detection protocols to enhance the sensitivity and specificity of histone lactylation detection and advance its clinical translation.

Similarly, the absence of target screening criteria constrains the clinical translation of histone lactylation. Many genes, sites, and enzymes associated with histone lactylation modifications have the potential to serve as disease biomarkers or therapeutic targets. However, unified standards and systematic validation frameworks for identifying the most clinically valuable core targets tailored to specific disease pathologies remain lacking. The expression heterogeneity of different lactylation sites (e.g., H3K18la, H4K12la, and H3K14la) across various diseases, as well as different subtypes of the same disease, is not well understood. This hinders the establishment of specific “site-disease” correlations.Finally, clinical validation remains insufficient. Most existing studies are based on cell lines and animal models and lack multi-center, large-sample clinical cohort validation. Normal reference ranges, diagnostic thresholds, and prognostic cutoff values for histone lactylation across different diseases have yet to be systematically established. Therefore, large-sample cohort studies are needed to determine baseline levels under normal physiological conditions. Marker levels only hold diagnostic significance when they are significantly above or below this threshold.

Conclusion and future directions

Histone lactylation, a post-translational modification of histones, was first discovered in 2019. Using lactate as the core substrate, it forms a crucial bridge between cellular metabolic reprogramming and epigenetic regulation. This represents a new type of epigenetic code that influences cell fate. This review summarizes the mechanism of histone lactylation and the regulatory system of modifying enzymes. It clarifies the core functions and substrate selectivity regulatory mechanisms of “writers,” “erasers,” and “readers.” Based on this information, the review systematically links histone lactylation to major benign and malignant gynecological diseases, revealing its regulatory mechanisms in malignant tumors, such as OC, CC, and EC, as well as in benign lesions, such as EMS and PCOS. Studies have shown that histone lactylation, which regulates the transcriptional activity of key genes, plays a significant role in the proliferation, migration, immune evasion, and treatment resistance of gynecological malignancies. At the same time, it is also implicated in the development of benign gynecological diseases. In addition to the benign and malignant gynecological diseases discussed in this review, a growing body of evidence suggests that histone lactylation also affects gene expression [100], immune phenotypes [151], and therapeutic resistance [122] in other cancers. Among these malignancies, breast cancer (BC), as a highly prevalent cancer in women, shares certain overlapping features with some gynecological malignancies, such as OC, CC and EC, in terms of hormonal regulation, genetic susceptibility, metabolic abnormalities, and the tumor-associated microenvironment [152]. Further studies have suggested that lactate accumulation and lactate-mediated histone lactylation can also participate in gene expression regulation and tumor progression in BC [153]. Therefore, findings from BC may provide complementary evidence beyond the main disease scope of this review and offer an extended perspective for understanding the “metabolic reprogramming–epigenetic regulation–tumor progression” axis in female-related malignancies. Moreover, in certain diseases, lactylation can interact with other modifications, including acetylation [55], ubiquitination [57], SUMOylation [58], and methylation [56], thereby jointly influencing chromatin status and target gene transcription. Lactylation may also affect chromatin accessibility or compaction through its interplay with methylation [154].

Furthermore, the dynamic and reversible nature of histone lactylation modification makes it a highly promising target for intervention. Integrating existing research findings reveals that strategies targeting lactate production, transport, and enzymes involved in histone lactylation modification show promise in reversing drug resistance, restoring immune responses, and inhibiting disease progression [60, 78, 92]. Some traditional Chinese medicine active components, such as tanshinone I, have been found to have anti-gynecological tumor effects by regulating the lactylation pathway. This provides a new mechanistic basis for combined treatment of gynecological tumors using traditional and modern medicine [73]. These findings deepen our understanding of the cross-regulation mechanism between metabolism and epigenetics in gynecological diseases and provide new ideas for developing diagnostic biomarkers and designing targeted treatment strategies for related diseases.

As mentioned earlier, although histone lactylation shows great potential for research in gynecological diseases, its clinical translation still faces many challenges, such as unclear molecular mechanisms, bottlenecks in targeted intervention, and insufficient validation of biomarkers. Future research should focus on the following areas: (1) Using integrated multi-omics analysis, mass spectrometry imaging, and big data analysis technologies combined with single-cell lactylation maps to systematically analyze the dynamic changes of histone lactylation in different subtypes and pathological stages of benign and malignant gynecological diseases. This analysis should clarify the correlations between histone lactylation and metabolites, target genes, and downstream signaling pathways. Additionally, it should screen for combinations of histone lactylation-related biomarkers with diagnostic and prognostic value. (2) Use CRISPR site-specific epigenetic editing technology to verify the functions of individual lactylation sites and modifying enzymes. Based on this information, develop highly specific tool compounds and precise intervention strategies for “writers,” “erasers,” and “readers.” This will improve the specificity and effectiveness of target regulation. At the same time, use emerging nanotechnology to achieve cell-selective drug delivery. This will enhance tumor local accumulation and reduce systemic toxicity. 3)Actively promote the research and development of new epigenetic drugs targeting histone lactylation. Combine lactylation-targeted drugs with immunotherapy, ferroptosis inducers, autophagy inhibitors, etc., to avoid the risk of pathological compensation from a single treatment and achieve synergistic enhancement. Currently, most related inhibitors are in the preclinical stage, and rigorous experiments and clinical data are urgently needed to support their safety and effectiveness. 4) Expand the scope of research on the gynecological TME. Building on existing studies of macrophages, T cells, and so on, further explore the expression characteristics and functional regulation of histone lactylation in immune cell subpopulations, such as B cells and dendritic cells. Additionally, analyze the modification mechanisms in other cell components, including tumor-associated fibroblasts, endothelial cells, and tumor stem cells. As we deepen our study of histone lactylation mechanisms, improve targeted tools, and advance clinical validation, we expect that diagnostic and therapeutic strategies based on histone lactylation will overcome existing obstacles and open new paths for the precise diagnosis and treatment of gynecological diseases.

Abbreviations

PTMs

Post-translational modifications

HDAC

Histone deacetylases

TME

Tumor microenvironment

ACSS2

Acyl-CoA synthetase short-chain family member 2

HATs

Histone acetyltransferases

CBP

CREB-binding protein

EMS

Endometriosis

PCOS

Polycystic ovary syndrome

OC

Ovarian cancer

EOC

Epithelial ovarian cancer

LDHB

Lactate Dehydrogenase B

PD-L1

Programmed death-ligand 1

PD-1

Programmed death-1

HGSOC

High-grade serous ovarian carcinoma

HR

Homologous Recombination

SEs

Super-enhancers

2-DG

2-deoxy-D-glucose

TCM

Traditional Chinese medicine

CC

Cervical Cancer

LDHA

Lactate dehydrogenase A

EC

Endometrial Cancer

USP39

Ubiquitin-specific protease 39

PGK1

Phosphoglycerate kinase 1

NHE7

Sodium-hydrogen exchanger 7

DNMT1

DNA methyltransferase 1

HMGB1

High mobility group protein 1

lncRNA

Long non-coding RNA

RASD2

Ras-related dexamethasone-induced 2

CTPS1

Cytidine triphosphate synthase 1

METTL3

Methyltransferase-like 3

PDAC

Pancreatic ductal adenocarcinoma

HK

Hexokinase

PK

Pyruvate kinase

MCTs

Monocarboxylate transporters

CTCF

CCCTC-binding factor

BC

Breast cancer

Authors’ contributions

Wanhui You: Conceptualization, Investigation, Validation, Visualization, Writing – original draft, Writing – review & editing. Siyu Wang: Supervision, Investigation, Validation, Visualization. Yue Zhang: Supervision, Validation, Writing – review & editing. Xin Su: Supervision, Validation, Writing – review & editing. Fangyuan Liu: Writing – review & editing, Project administration. Danni Ding: Writing – review & editing, Project administration. Fengjuan Han: Funding acquisition, Investigation, Methodology, Writing – review & editing, Resources, Supervision, Project administration. Ying Guo: Validation, Visualization.

Funding

This study was supported by the following grants:

1. National Natural Science Foundation of China (Grant No. 8257156377): Mechanism study of effective components of Lichong Sheng Sui Decoction in regulating oxidative stress-driven cold-hot transformation of ovarian cancer immune microenvironment based on multi-scale modeling.

2. Traditional Chinese Medicine Evidence-Based Capacity Improvement Project (Grant No. 202324): Evidence-based study on traditional Chinese medicine in the treatment of dominant disease “Zhengjia” (ovarian endometriotic cyst).

Data availability

No datasets were generated or analysed during the current study.

Code availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.