Lactylation’s role in bone health and disease: mechanistic insights and therapeutic potential

Lactylation regulates osteogenic differentiation

Stem cell differentiation is an energy-intensive process, with the energy sources relying on pathways such as aerobic glycolysis and oxidative phosphorylation (Ning et al., 2022). For example, self-renewing hematopoietic stem cells (HSCs) primarily rely on anaerobic glycolysis to maintain their quiescent state. However, during HSC differentiation, cells shift toward engagement of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) to generate high levels of ATP, reflecting increased energy demands (Casati et al., 2011). Similarly, differentiated osteoclasts secrete large amounts of acids and proteolytic enzymes and require substantial energy, relying predominantly on OXPHOS as the main bioenergetic mechanism. In differentiating osteoblasts, a distinct metabolic pattern is observed: these cells are characterized by the presence of mitochondria with high transmembrane potential and a sharp increase in oxygen consumption (Arnett & Orriss, 2018). Nevertheless, even under aerobic conditions, osteoblasts primarily metabolize glucose through glycolysis into pyruvate. Lactate is generated from pyruvate through the glycolytic pathway, particularly under hypoxic conditions or during metabolic states characterized by rapid energy demands, where glycolysis produces ATP more quickly than oxidative phosphorylation (Guntur et al., 2018; Shen, Hu & Karner, 2022). These metabolic shifts, especially during stem cell differentiation and bone cell lineage commitment, are associated with changes in lactate production Lactate, previously considered a metabolic waste product, has recently been found to play a key role in energy metabolism (Choi et al., 2024; Loeffler et al., 2018; Neto et al., 2023), particularly in the osteogenic differentiation of stem cells. Lactylation has been shown to be closely associated with cellular energy status and metabolic activity (Li et al., 2024b), excessive lactate may contribute to the dynamic regulation of histone lactylation.

For instance, lactate-derived lactylation on histone lysine residues promotes gene transcription, increasing the expression of osteogenic differentiation-related transcription factors such as Runx2, JunB, and other osteogenesis-associated genes (Li et al., 2025), which in turn promotes the differentiation of stem cells into osteoblasts (Nian et al., 2022; Wu et al., 2023a). It is well known that lactate dehydrogenase A (LDHA) converts pyruvate into lactate, and within the cell, the levels of LDHA are closely associated with both the osteogenic differentiation and histone lactylation levels. Histone H3 lysine 18 (H3K18) is a key site for lactylation, and its marking indicates the activation of gene expression (Wang et al., 2024a). During osteogenic differentiation in various cell types, the increase in LDHA levels enhances both osteogenic differentiation and histone lactylation levels. Conversely, when LDHA is inhibited, both levels decrease. Chromatin immunoprecipitation (ChIP) assays have shown that LDHA activates osteogenic gene expression by influencing H3K18 lactylation (H3K18la) (Minami et al., 2023; Nian et al., 2022) (Fig. 1).

The terms “Writer” and “Eraser” refer to enzymes or proteins responsible for adding, promoting, or suppressing lactylation modifications. Among the “Writers”, the role of histone acetyltransferase (p300) is particularly notable. For example, in the C2C12 myoblast cell line, the introduction of Ep300 siRNA into C2C12 cells suppressed the expression of Ep300 mRNA, lactylation levels, and osteogenesis-related gene expression. However, during this process, both intracellular and extracellular lactate concentrations remained unaffected, indicating that p300 is a key factor controlling lactylation levels (Minami et al., 2023). For the “Erasers”, compounds such as the p300 inhibitor A485 can inhibit UDP-glucose dehydrogenase (UGDH) lactylation in vitro and in vivo, rescuing chondrocyte extracellular matrix degradation and delaying the progression of osteoarthritis (OA). Furthermore, pyruvate dehydrogenase kinase inhibitors (DCA) and histone deacetylases (HDACs) have been found to suppress lactylation levels, although their impact on osteogenic differentiation remains uncertain (Moreno-Yruela et al., 2022; Wang et al., 2022b; Zhang et al., 2019).

Existing evidence suggests that p300 is a relatively clear “Writer” of lactylation modifications. Its mechanism likely involves the interaction between p300 and GTP-specific succinyl-CoA synthetase (GTPSCS), forming a functional lactyltransferase complex in vivo, which promotes histone lactylation (Liu et al., 2025; Zong et al., 2025). Lysine acetyltransferases (KAT) and alanylal-tRNA synthetase (AARS) also exhibit “Writer” roles, but their research in the bone biology field is limited (Ren, Tang & Zhang, 2025). As for the “Erasers”, compounds such as A485 inhibit p300, thereby indirectly suppressing lactylation levels rather than acting directly. DCA has yet to be shown to suppress osteogenic differentiation, and both A485 and DCA are small molecules, not enzymes or proteins. Therefore, HDACs are currently considered the most defined “Erasers” (Ren, Tang & Zhang, 2025). Additionally, SIRT2 is a newer “Eraser”, but its catalytic efficiency is lower than that of HDACs (Zong et al., 2025). In conclusion, further exploration of “Erasers” in the osteogenic field is needed (Cui et al., 2021; Hu et al., 2024; Minami et al., 2023; Yang et al., 2022; Zhang et al., 2019).

Currently, no specific bone-specific regulators have been identified to regulate the lactylation response. Lactylation levels are primarily controlled by lactate levels and enzymes that promote lactylation modifications, with lactate levels being mainly influenced by factors such as LDH and pyruvate kinase (PK) (Brooks et al., 1999; Llanos et al., 1993).

Lactation and osteoclasts

While emerging studies have explored the role of lactylation in regulating osteoblast function, direct evidence for the regulation of osteoclasts by lactylation remains scarce. Nevertheless, this is an intriguing and promising area of investigation. Recent studies indicate that RANKL induces a metabolic shift in osteoclasts toward accelerated glycolytic metabolism (Taubmann et al., 2020), and inhibition of glycolysis has been shown to ameliorate osteoclast activity and bone resorption. Additionally, a recent study by Shen et al. (2025) reported that Mg²⁺ promotes lactate production in osteoclasts, leading to increased histone lactylation and suppression of osteoclastogenesis (Fig. 1).

Although direct studies specifically addressing lactylation in osteoclasts are currently limited, interest in the role of lactylation in bone biology is rapidly expanding. Moreover, regulation of osteoclast function through other PTMs provides structural and mechanistic support for the potential importance of lactylation. For example, Williams, Nishu & Rahman (2011) demonstrated that inhibition of HDACs, known erasers of lactylation and acetylation, suppresses osteoclastogenesis by upregulating the expression of C/EBP-β and MKP-1. Similarly, Kim et al. (2011) showed that RANKL induces NFATc1 acetylation via histone acetyltransferases (HATs), enhancing NFATc1 stability and transcriptional activity during osteoclast differentiation. These findings suggest that metabolism-sensitive PTMs, including lactylation, may play critical regulatory roles in osteoclast biology and highlight important directions for future research.

Lactate plays a complex role in bone metabolism, particularly in the differentiation, activity, and function of osteoclasts. In an acidic environment, the activity of osteoclasts is enhanced, and the accumulation of lactate can lower the local pH value, which may promote the fusion, differentiation, activity, maturation, and function of osteoclasts (Arnett & Orriss, 2018; Yuan et al., 2016). Interestingly, in osteoclasts, lactate accumulation and the resulting decrease in pH have opposite effects compared to the lactylation induced by lactate accumulation, leading to conflicting results. Therefore, the relationship between lactylation and osteoclasts remains to be further clarified.

Lactylation and immune cell regulation

Bone homeostasis is a part of bone metabolism, where the roles of osteoblasts and osteoclasts are self-evident (Shahi, Peymani & Sahmani, 2017). However, the regulation of bone homeostasis is also inseparable from the function of immune cells, among which macrophages are closely related to bone homeostasis (Bozec & Soulat, 2017; Gu, Yang & Shi, 2017; Hu et al., 2023; Hu et al., 2022). For instance, regarding osteoblasts, M2-type macrophages can secrete osteogenic inducers such as BMP-2, thereby stimulating the expression of osteogenic gene phenotypes in osteoblasts, such as Runx2, ALP, and OCN, affecting osteoblast differentiation and osteogenic activity. In contrast, M2-type macrophages can also secrete anti-inflammatory factors like IL-4 and IL-13, with IL-4 capable of preventing osteoclast formation by activating the NF-κB pathway. In opposition to M2-type, M1-type macrophages promote the generation of osteoclasts by secreting pro-inflammatory factors such as TNF-α and IL-1β, and inhibit the expression of osteogenic factors like Runx2 and IGF-1, thereby suppressing osteoblast production. M1-polarized macrophages can also mediate the RANKL/RANK system, causing osteoclast-induced bone damage (Bozec & Soulat, 2017; Hu et al., 2023; Hu et al., 2022). Thus, it is evident that macrophages can influence bone homeostasis by affecting the metabolic states of osteoblasts and osteoclasts.

Recent research has found that lactylation is an important regulator of macrophages, on the one hand, lactylation can regulate the phenotype of macrophages, and on the other hand, it can also regulate the metabolism of macrophages (Xu et al., 2024). Firstly, as a metabolic product, lactate accumulates in an acidic environment and can alter the phenotype of macrophages (Wei et al., 2024). Studies have shown that through glycolysis and the production of lactate, the B-cell adapter for PI3K (BCAP) promotes histone lactylation, which facilitates the transition of inflammatory macrophages to M2-type macrophages, beneficial for alleviating intestinal inflammation (Irizarry-Caro et al., 2020). Additionally, in a mouse model of colon cancer, lactate can also promote the M2 polarization of macrophages through the lactylation of retinoic acid-inducible gene 1 (RIG-1) (Gu et al., 2024). These transformations reveal a macro-level shift in the balance between the two types of macrophages within inflammatory models. Intracellularly, increased mitochondrial fission also leads to changes in lactylation levels, thereby inducing M2 macrophage polarization (Susser et al., 2023). The shift towards the M2 phenotype enables macrophages to more effectively promote anti-inflammatory responses and reparative functions (Liu et al., 2019; Schlundt et al., 2021).

Moreover, the production of lactate is closely associated with local hypoxic conditions, which not only promote lactate generation but also induce macrophages to produce more M2-type cells (Riboldi et al., 2013; Zhou et al., 2022). Studies have found that in hypoxic environments, macrophages can regulate the expression of osteoblast-related factors through HIF-1α (Dehne & Brüne, 2009), such as BMP-2 and VEGF. These factors not only directly participate in the osteogenic process but also promote angiogenesis, providing essential nutrients and oxygen to the bone (Chen et al., 2012; Wang et al., 2020). Therefore, the roles of hypoxia and lactate play a crucial dual role in maintaining bone homeostasis (Karner & Long, 2018). Further analysis of the metabolic effects of lactylation on macrophages reveals that lactylation has an important role in regulating gene expression in macrophages. H3K18la drives M2-like gene expression, such as Arg1, during M1 macrophage polarization, and this induction process is time-dependent (Zhang et al., 2019). Arg1, as a negative regulator of osteoclasts, can inhibit osteoclast differentiation (Yeon, Choi & Kim, 2016). In another study, tumor-derived lactate drove macrophages to downregulate RARγ gene transcription through histone lactylation, thereby promoting tumor growth (Li et al., 2024a), and RARγ also plays an important role in promoting osteoblast differentiation (Green et al., 2017). Although this was observed in a tumor model, the ability of lactylation to affect RARγ expression provides a new possibility for future research on the impact of lactylation on bone metabolism. Additionally, in a model of infected macrophages, the removal of lactylation at the histone H4K8 site through Sirtuin 2 (SIRT2) reduced the chemotactic ability of macrophages. Therefore, targeting SIRT2 and H4K8la modifications may help control macrophage-mediated inflammation (Wenting et al., 2023). In summary, lactylation affects macrophage phenotypes and metabolism through multiple pathways, thereby creating a benign repair microenvironment. Although this regulation is not within the bone microenvironment, it demonstrates the great potential of lactylation in maintaining bone homeostasis.

In addition to macrophages, T cells also play a pivotal role in maintaining bone homeostasis (Li, Pi & Li, 2021), influencing the functions and metabolism of osteoblasts and osteoclasts (Fischer et al., 2019). Among different T cell subsets, such as CD4+T cells, particularly Th17 cells, promote osteoclastogenesis by secreting factors like IL-17 and RANKL. Binding of RANKL to its receptor RANK stimulates the differentiation of osteoclast precursors into mature osteoclasts, thereby enhancing bone resorption. RANKL is a crucial factor for osteoclast formation, while OPG acts as its antagonist (Takegahara, Kim & Choi, 2022). The presence of T cells can promote the expression of OPG, inhibit the action of RANKL, and reduce osteoclast activity (Zhang et al., 2020). Furthermore, it is well-established that T-regulatory cells (Tregs) promote the proliferation and differentiation of osteoblasts by secreting anti-inflammatory cytokines such as TGF-β and IL-10, thereby facilitating bone formation and contributing to the maintenance of bone density and quality (Huang et al., 2022; Zhu et al., 2020). Additionally, T cells can regulate the production of RANKL and OPG by influencing the function of dendritic cells and other immune cells, thereby affecting osteoclastogenesis (Walsh & Choi, 2014).

Lactylation has been found to regulate the function of Treg cells. For instance, in the tumor microenvironment, lactylation can enhance TGF-β signaling by modulating specific proteins in Treg cells, such as MOESIN, thereby influencing the differentiation, stability, and function of Treg cells (Gu et al., 2022). Furthermore, lactylation not only affects the function of Treg cells but may also impact immune homeostasis by regulating the metabolic states of other T-cell subsets (Chen et al., 2022b; Wu, Huang & Zhao, 2023). Such effects hold significant regulatory importance for the bone marrow microenvironment, bone metabolism, and bone homeostasis (Fischer et al., 2019).

In the experimental autoimmune uveitis (EAU) mouse model, the lactylation level in CD4+ T cells significantly increases. The use of glycolysis inhibitors, such as dichloroacetic acid (DCA), a pyruvate dehydrogenase kinase inhibitor, can reduce the lactylation level in CD4+ T cells and inhibit the differentiation of TH17 cells. Conversely, blocking mitochondrial metabolism, for example with rotenone, increases the lactylation level in CD4+ T cells and promotes the differentiation of TH17 cells, alleviating the inflammatory process of EAU. Lactylation can influence the expression of specific genes in T cells by differentially regulating the binding of lactylated proteins at the Lys164 site to the promoters of TH17-related genes, such as Tlr4 and Runx1 (Fan et al., 2023), which are crucial for regulating bone metabolism and homeostasis (Tang et al., 2021; Tominari et al., 2024). In another study, lactate has a significant impact on T cells, particularly pro-inflammatory Th17 cells. Lactate reprogramming of Th17 cell metabolism and epigenetic status by inhibiting IL-17A production, inducing Foxp3 expression, and promoting histone H3K18la results in the transformation of these cells towards an immunosuppressive Tregs phenotype, exhibiting an anti-inflammatory effect in intestinal inflammation models (Lopez Krol et al., 2022). For CD8 T cells, lactylation significantly affects their metabolic status. In activated CD8 T cells, lactate produced through glycolysis increases, whereas in memory CD8 T cells, lactate produced through mitochondrial metabolic pathways such as oxidative phosphorylation and fatty acid oxidation increases. Lactylation also regulates the function of CD8 T cells by affecting the expression of specific genes. For instance, H3K18la and H3K9la are enriched in the promoter regions of effector CD8 T cell genes such as Gzmb and IFN-γ, and positively correlate with the expression levels of these genes (Raychaudhuri et al., 2024). Gzmb and IFN-γ exhibit potent immune functions against the bone marrow microenvironment or intraosseous tumors (Chen et al., 2022a), while IFN-γ also contributes to osteoblast differentiation and chondrogenesis (Maruhashi et al., 2015) (Table 1).

Therefore, understanding the impact of lactylation on macrophages and various T-cell subsets will provide us with a new perspective to deepen our comprehension of their complex roles in bone metabolism and homeostasis. Although the regulatory mechanisms of lactylation on macrophages and T-cells have been partially elucidated, further research is required to fully understand how lactylation directly or indirectly affects bone homeostasis through macrophages and T-cells. However, it can be speculated that lactylation may influence the interaction between these immune cells and bone cells by modulating the function and activity of macrophages and T-cells (Chen et al., 2021a), ultimately impacting bone homeostasis.

Lactylation and periodontitis

Periodontitis is an inflammatory disease caused by bacterial infection, typically accompanied by redness, swelling, bleeding of the gums, and bone loss (Salvi et al., 2023). The presence of periodontal pathogens and activation of the host immune response lead to the intensification of local inflammatory reactions and accumulation of metabolites (Ji, Choi & Choi, 2015). During the pathological process of periodontitis, lactic acid produced by bacterial metabolism causes acidification of the local environment, thereby affecting related physiological activities (Ishikawa et al., 2021). As the final product of glycolysis, the increased concentration of lactic acid in the periodontitis microenvironment results in elevated levels of lactylation. This change in modification significantly impacts cell function and inflammatory responses (Chen et al., 2022b).

In the periodontitis microenvironment, macrophages serve as crucial immune cells, and changes in their polarization status have a significant impact on inflammation progression and tissue repair (Schlundt et al., 2021). Intriguingly, lactylation has been demonstrated in numerous studies to regulate the polarization state and function of macrophages, thereby inhibiting inflammation progression and promoting tissue repair. Research shows that in a rat periodontitis model, after inhibiting the lactylation “writer” enzyme P300 in Raw264.7 cells, the lactylation level decreased due to the lack of a “starter”, leading to increased expression of inflammatory cytokines IL-1β, IL-6, and TNF-α, which are key pro-inflammatory factors in the inflammatory response. Simultaneously, the levels of M1 macrophage-associated factors such as CD86 and iNOS increased, while those of M2-associated factors Arg1 and CD206 decreased (Liu et al., 2024b). This experiment directly reveals a possible mechanism of lactylation in the development of periodontitis, providing a more comprehensive understanding of the disease. In another study, transfection of macrophages with a novel ncRNA from Porphyromonas gingivalis, namely msRNA P.G_45033, increased lactate and lactylation levels in macrophages, inducing an increase in β-amyloid protein (Aβ) production (Zhang et al., 2023). Elevated Aβ levels have a significant impact on bone loss (Li et al., 2014; LLabre et al., 2020). These studies link periodontitis, macrophages, and lactylation, uncovering a novel mechanism of lactylation’s role in alveolar bone resorption in periodontitis.

Furthermore, lactylation can influence bone resorption and reconstruction processes in periodontal tissues by regulating osteogenic differentiation of stem cells. For instance, in periodontitis, proanthocyanidins can ameliorate the inhibition of osteogenic differentiation in PDLSCs under lipopolysaccharide (LPS)-induced inflammatory conditions. Specifically, proanthocyanidins achieve this by restoring lactylation in PDLSCs, upregulating the Wnt/β-catenin pathway, and increasing the expression of the downstream target gene RUNX2, thereby promoting alveolar bone regeneration (Wu & Gong, 2024). Similarly, scopolamine (SCO) treatment of PDLSCs also favors periodontal tissue regeneration, with a process akin to the aforementioned experiment with proanthocyanidins (Wu & Gong, 2024). Additionally, histone lactylation, by mediating lactate levels, can regulate alveolar bone remodeling during orthodontic tooth movement (Zhai et al., 2022). These studies highlight the significance of lactylation in the development and improvement of periodontitis, providing a more comprehensive understanding of the pathogenesis of periodontitis and potential strategies for targeted therapy.

However, these studies also have limitations. First, most research is based on cell or animal models (such as Raw264.7 cells), with insufficient direct evidence from human periodontal tissue. Second, there is limited research on the direct effects of lactylation on osteoclasts (as opposed to osteoblasts), and the bidirectional regulation of bone resorption and formation has not been fully confirmed. Finally, high lactate environments may exacerbate inflammation (Arnett & Orriss, 2018; Yuan et al., 2016), suggesting that lactylation could have opposing effects due to differences in the microenvironment, necessitating more detailed spatiotemporal dynamic studies.

Lactylation and osteoporosis

Osteoporosis is a prevalent bone disease primarily characterized by decreased bone mass and deterioration of bone microarchitecture, leading to increased bone fragility and susceptibility to fractures. As individuals age, bone metabolism gradually slows down, resulting in progressive bone mass loss and an elevated risk of osteoporosis. This risk further intensifies, particularly in women after menopause (Lorentzon et al., 2022; Sànchez-Riera et al., 2010). Additionally, several metabolic syndromes, including central obesity, hyperglycemia, hypertension, and dyslipidemia, have been associated with osteoporosis (Wong et al., 2016).

Lactate can act as a signaling molecule to influence bone metabolism. Studies have shown that lactate, beyond serving as an energy source, also functions as a signaling molecule impacting various cellular functions. In the development of osteoporosis, lactate may regulate bone mineral density by affecting the activity of osteoblasts and osteoclasts (Taubmann et al., 2020; Wu et al., 2017). Intriguingly, lactate can influence bone cell function through histone lactylation. Research has found that endothelial cells (ECs) produce lactate during glycolysis and permeate it into bone tissue through blood vessel walls, triggering H3K18la in bone marrow mesenchyml stem cells (BMSCs), thereby activating the expression of bone formation-related genes. Specific mechanisms include lactate-induced expression of bone formation-related genes such as COL1A2, COMP, ENPP1, and TCF7L2 in BMSCs, which play crucial roles in bone mineralization and formation. Conversely, when ECs glycolysis are inhibited, serum lactate levels decrease, along with reduced H3K18la in BMSCs, negatively impacting bone formation. By restoring lactate levels, such as through exogenous lactate supplementation or high-intensity interval exercise, osteoporotic symptoms can be partially reversed. Furthermore, clinical data also indicate that osteoporotic patients exhibit lower serum lactate levels, decreased H3K18la levels in BMSCs, and reduced expression of related genes, further supporting the important role of lactylation in bone formation. Regarding bone vascular density, mice exhibit decreased bone vascular density and reduced expression of PKM2, a regulatory factor of endothelial glycolysis. This suggests that the glycolysis process in endothelial cells has a significant impact on bone vascular density, and lactate, as one of the products of glycolysis, may be involved in this process (Wu et al., 2023a).

In terms of improving osteoporosis, high-intensity interval training (HIIT) has been shown to enhance bone mineral density (BMD) in osteoporotic animals through lactate-mediated anabolic bone effects, suggesting that lactate produced during exercise may promote bone health by enhancing osteoblast activity and mineralization capacity through promoting protein lactylation (Huang et al., 2023; Zhu et al., 2023). In addition, hypertension, which is also a common condition among the elderly, is closely related to osteoporosis. Possible factors contributing to this relationship may include nutrient intake, cytokine release, or signaling pathway activation (Do Carmo & Harrison, 2020; Nakagami & Morishita, 2013; Varenna et al., 2013). Exercise increases lactate production and induces NICD lactylation, thereby inhibiting NOTCH signaling, upregulating the expression of angiogenic factors, promoting angiogenesis, and lowering blood pressure (Liu et al., 2024c).

Overall, lactylation plays a significant role in regulating osteoporosis. Through various mechanisms such as promoting osteoblast differentiation, regulating bone vascular density, and facilitating bone formation, lactylation contributes to maintaining bone health and homeostasis. Furthermore, through exercise, lactate accumulation in the body can enhance lactylation, which may directly influence bone cell activity, offering a potential means of alleviating osteoporosis. From an indirect perspective, lactylation can also affect diseases associated with osteoporosis, such as improving hypertension, which in turn may help restore bone health (Ilić, Obradović & Vujasinović-Stupar, 2013). In conclusion, these studies demonstrate the link between lactylation, osteoporosis, and exercise, positioning lactylation as a new “mediator” for osteoporosis treatment.

Histone lactylation and metabolism: which comes first, the chicken or the egg?

Metabolism influences post-translational modifications of histone proteins by regulating the availability of donor substrates, whereas histone modifications, in turn, can impact metabolic pathways by modulating the expression of key metabolic enzymes and altering metabolite pools. Although the detailed crosstalk between histone lactylation and cellular metabolism falls outside the scope of this review, it is important to note that metabolic reprogramming alone can significantly affect stem cell differentiation. For a more comprehensive discussion on the interplay between metabolism and cell fate decisions, readers are referred to the review by Wu, Ocampo & Belmonte (2016)

However, emerging evidence increasingly supports the notion that histone lactylation acts as a primary regulatory mechanism in bone cell differentiation, rather than being a mere byproduct of metabolic changes. For example, in a study by Minami et al. (2023) silencing the histone lactylation enzyme p300 significantly inhibited osteoblast differentiation. This was accompanied by a marked reduction in histone lactylation levels, suggesting that p300-mediated lactylation is essential for the osteogenic process. In a more recent and mechanistically thorough study, (Wu et al., 2023a) demonstrated that endothelial cell-derived lactate promotes osteogenesis in BMSCs through histone lactylation. Knockdown of MCT1, the monocarboxylate transporter responsible for lactate uptake, reduced intracellular lactate levels, suppressed H3K18la modification, and significantly decreased ALP and ARS staining in BMSCs treated with conditioned medium from bone microvascular endothelial cells (BMECs). Furthermore, genetic deletion or pharmacological inhibition of p300 led to reduced histone lactylation and impaired osteogenic differentiation under the same conditions. Together, these studies provide compelling functional evidence that lactylation is not merely reflective of metabolic flux but plays a direct and causative role in regulating bone cell fate.

Although current evidence directly linking histone lactylation to osteoblast metabolism and differentiation remains limited, owing to the relative novelty of the field, emerging insights from related epigenetic modifications suggest a plausible regulatory axis. For instance, in calcific aortic valve disease, mechanical stress sensed through the Piezo1 ion channel promotes glutaminolysis and acetyl-CoA production, enhancing H3K27 acetylation at osteogenic genes mediated by RUNX2 in valve interstitial cells (Zhong et al., 2023). Similarly, hypoxia-induced citrate export from mitochondria to the cytoplasm increases cytosolic acetyl-CoA, supporting H3K27 acetylation and osteogenic gene expression in mesenchymal stem cells (Pouikli et al., 2022). These examples highlight how metabolic shifts can regulate histone modifications to control cell fate decisions. However, whether histone lactylation follows a similar paradigm in osteoblasts or osteoclasts remains an open question that future studies will need to address.

Limitations

To date, no in vivo models have directly and specifically demonstrated the causal role of histone lactylation in bone formation or resorption. While lactylation is a downstream product of lactate metabolism, its functional dissection in vivo remains challenging due to multiple overlapping mechanisms and confounding metabolic effects.

Strategies to inhibit histone lactylation typically involve targeting lactylation “writers” or “erasers” through genetic or pharmacological approaches, or modulating intracellular lactate availability. However, global knockout of lactylation “writers” CBP/p300 is embryonically lethal, limiting the use of conventional knockout models (Kasper et al., 2006). A recent study demonstrated that conditional deletion of p300 in osteoblasts leads to significantly reduced bone mass and mechanical strength, highlighting its essential role in bone homeostasis (Zhang et al., 2024). Nevertheless, as p300 mediates not only lactylation but also histone acetylation and other acylations, its deletion results in widespread epigenetic alterations, thereby confounding efforts to attribute phenotypic effects specifically to the loss of histone lactylation. Moreover, p300 has been shown to promote osteogenesis through transcriptional coactivation of signaling pathways such as SMAD1 and Osterix, further complicating its interpretation as a lactylation-specific effector in bone biology (Quan et al., 2023).

Inhibiting lactate transport (e.g., via MCT1) or synthesis (LDHA) represents another approach, though these strategies also have limitations. MCT1 blockade may impair mitochondrial biogenesis and metabolic flux, thereby indirectly altering cell function (Zhang et al., 2024), and it cannot prevent intracellular lactate production. Moreover, osteoblasts rely primarily on glycolysis for energy, while osteoclasts depend more on oxidative phosphorylation (Lee et al., 2017), suggesting that LDHA inhibition may offer a more targeted model in osteoblasts. In vitro studies have shown that LDHA knockdown impairs ALP activity and mineralized nodule formation, supporting a role for lactylation in osteoblast differentiation (Nian et al., 2022). However, a bone cell-specific LDHA knockout model in vivo has not yet been reported, due to the broad role of LDHA in cellular energy metabolism and the risk of disrupting systemic physiological processes (Kwarteng & Agathocleous, 2023). It is also important to recognize that bone cells are influenced by extracellular lactate originating from non-bone cells such as endothelial cells and skeletal muscle cells. These exogenous lactate sources can be taken up via MCTs, or extracellular vesicles (EVs) and drive histone lactylation in osteoblasts or BMSCs (Wu et al., 2023a). Therefore, osteoblast- or osteoclast-specific LDHA deletion may not eliminate functional lactylation.

Furthermore, lactate itself can activate signaling pathways independent of histone modification. For instance, it binds to GPR81, a lactate-sensing receptor on osteoblasts, and enhances osteogenic activity through PKC-Akt signaling, independently of lactylation (Wu et al., 2018). Hence, in vivo suppression of lactate production or transport introduces multiple metabolic and signaling confounders that limit our ability to attribute observed effects solely to histone lactylation.

Nevertheless, indirect evidence supports the physiological relevance of histone lactylation in bone. Wu et al. (2023a) demonstrated that endothelial cell-specific knockout of PKM2, a key glycolytic regulator, reduced lactate production, which in turn decreased H3K18la levels in BMSCs and impaired osteogenesis. They further identified COL1A2, COMP, ENPP1, and TCF7L2 as downstream targets of H3K18la via GO enrichment and transcriptome analysis. Rescue experiments using exogenous lactate and PKM2 overexpression confirmed that endothelial cell-derived lactate promoted osteogenesis via histone lactylation.

Although these findings remain indirect, the experimental strategy is consistent with approaches used in multiple studies across different systems to investigate lactylation, including myocardial infarction, sepsis, and cancer models (Hao et al., 2024; Wang et al., 2022b; Yang et al., 2022; Zhang et al., 2019).

Perspectives

Lactylation, along with other post-translational modifications such as acetylation, phosphorylation, and methylation, may collectively participate in complex gene regulatory networks (Chen et al., 2022b; Liu et al., 2022). Future research directions should include exploring the synergistic or antagonistic effects of lactylation with these modifications, especially in regulating chromatin states, gene expression, and cell fate determination. By integrating the interactions among multiple post-translational modifications, it may be possible to uncover more complex cellular metabolic and signaling pathways (Cheng et al., 2023; Wu et al., 2023b).

With the increasing incidence of metabolic diseases such as diabetes and obesity, the potential role of lactylation in these diseases has garnered significant attention (Wu et al., 2023b). Future research may focus on elucidating how lactylation participates in regulating metabolic imbalances, particularly its pivotal role in the metabolic reprogramming of osteoblasts (Sasa, Kato & Yamada, 2024). By modulating the levels of lactylation modifications, it may be possible to restore metabolic balance, thereby slowing down or reversing the progression of metabolic diseases. Furthermore, the regulation of lactylation may also be applied to enhance therapeutic effects on insulin resistance (Maschari et al., 2022). Additionally, the regulatory role of lactylation in inflammatory responses provides potential intervention pathways for the treatment of chronic inflammatory diseases. By inhibiting excessive inflammatory responses through the modulation of lactylation, lactylation modifications may be used in the treatment of inflammatory diseases such as rheumatoid arthritis (Wang et al., 2024b).

In summary, as an emerging post-translational modification, lactylation demonstrates its significant role in metabolic regulation, gene expression, and disease progression. With the further elucidation of its regulatory mechanisms and biological functions, its potential for clinical application will continue to increase, especially in the fields of bone regeneration, immunology, and metabolic disease treatment. As technological advancements progress, future research is expected to uncover the broader impacts of lactylation in cellular physiology and pathology, and provide new insights for disease treatment (Gong et al., 2024; Hu et al., 2024).