Lactylation-mediated miRNA regulation in cancer therapy resistance

Abstract

Therapeutic resistance in cancer is increasingly understood as a dynamic outcome of the interplay among tumour metabolism, epigenetic regulation, and immune modulation, rather than a consequence of genetic mutations alone. At this intersection, lactylation-a recently discovered lactate-derived post-translational modification (PTM)-acts as a molecular bridge linking metabolic rewiring to transcriptional and post-transcriptional control. Meanwhile, microRNAs (miRNAs) have emerged as essential regulators of metabolic adaptation and epigenetic plasticity. However, the interaction between lactylation and miRNA networks remains largely underexplored. Herein, we present a comprehensive and structured assessment of this emerging interdisciplinary field. We begin with a focused overview of tumour metabolic reprogramming and the enzymology of lactylation, establishing the biochemical context for its regulatory functions. We then examine how miRNAs interpret and reinforce metabolic cues, particularly through three interrelated regulatory frameworks. Lactylation of histones and DNA repair proteins has been shown to activate oncogenic miRNA clusters; these same miRNAs, in turn, enhance glycolytic flux and fine-tune the activity of lactylation enzymes, forming bidirectional feedback loops. Under stress conditions such as hypoxia or chemotherapy, lactate accumulation selectively suppresses DNA-repair-targeting and Pro-apoptotic miRNAs, stabilising BRCA1/RAD51-mediated repair programs. Furthermore, lactylation-dependent miRNA signals disseminate via extracellular vesicles, contributing to T cell exhaustion and macrophage M2 polarisation, thus shaping an immunosuppressive tumour microenvironment. Based on these converging mechanisms, we highlight potential therapeutic strategies, including the co-targeting of LDHA and oncogenic miRNAs (e.g., nanoparticle-mediated delivery of anti-miR-21), as well as liquid biopsy-based monitoring of circulating H3K18la and miRNA signatures to predict emerging resistance. By integrating metabolic, epigenetic, and immunologic perspectives, we position lactylation-miRNA crosstalk as a central regulatory axis in cancer therapy resistance and offer a conceptual framework to inform the development of future mechanism-driven interventions.

Introduction

Cancer remains a leading cause of mortality worldwide, with therapeutic resistance posing a formidable challenge to effective treatment [1–3]. In metastatic cancers, resistance mechanisms contribute to treatment failure in over 90% of cases, accounting for the vast majority of cancer-related deaths [4, 5]. Therapy resistance is not solely driven by genetic mutations, but also the result of metabolic adaptation and epigenetic reprogramming, which collectively allow tumor cells to escape treatment-induced stress and promote disease progression [3, 5, 6]. Elucidating the role of these adaptive mechanisms in therapy resistance is crucial to informing the development of novel therapeutic strategies to overcome treatment failure.

Recent studies have identified lactylation, an emerging PTM, as a key modulator of tumor metabolic reprogramming [7, 8]. Derived from lactate, a metabolic byproduct of aerobic glycolysis (Warburg effect), lactylation has emerged as a regulator of epigenetic modifications, influencing gene expression and cellular plasticity [8, 9]. As metabolic reprogramming is a hallmark of cancer progression and therapy resistance, lactylation introduces an additional layer of metabolic-epigenetic regulation in tumor adaptability, representing a promising yet underexplored avenue for cancer research.

MiRNAs are critical regulators of post-transcriptional gene expression, playing a pivotal role in epigenetic control [10, 11]. These small non-coding RNAs modulate key biological processes, including cell cycle regulation, apoptosis, and DNA repair, all of which are directly involved in therapy resistance [10, 12]. The interplay between lactylation and miRNA-mediated regulation adds another dimension to cancer cell survival strategies, influencing tumor adaptability and therapeutic response.

Here, we investigate the interplay between lactylation and miRNA function in therapy resistance. Specifically, we examine how lactylation influences miRNA processing, stability, and regulatory activity, and whether lactylation dynamics modulate miRNA networks to affect DNA damage repair and cell survival pathways. Furthermore, we evaluate whether lactylation-mediated miRNA modifications could serve as candidate biomarkers or therapeutic targets for overcoming cancer treatment resistance.

Dynamic regulation of lactylation in cancer

Biochemical basis of lactylation

Lactylation, a newly recognized PTM, is intrinsically connected to metabolic reprogramming in cancer, particularly in the context of the Warburg effect [8, 9]. This phenomenon describes the reliance of cancer cells on glycolysis and lactate production despite oxygen availability, leading to sustained lactate accumulation [13]. Beyond serving as a metabolic byproduct, lactate functions as a key signaling molecule in the tumor microenvironment (TME), influencing cellular behavior [14–16]. Tumor-associated acidosis further amplifies lactate buildup, fostering an environment that facilitates adaptive responses via lactylation [17, 18]. This metabolic adaptation plays a pivotal role in tumor progression and therapy resistance [8, 9].

Lactylation is governed by a coordinated enzymatic system that modulates its dynamic balance within cells. Lactyltransferases, such as TIP60 (a histone acetyltransferase), catalyze the covalent attachment of lactate moieties to target proteins, while de-lactylases, such as HDAC3 (a histone deacetylase), counteract this modification [19]. The interplay between these enzymes fine-tunes lactylation levels, impacting both cellular metabolism and key regulatory pathways such as gene expression and DNA repair [19]. This tightly regulated enzymatic network contributes to the adaptive responses of cancer cells to environmental stresses, including therapeutic resistance.

Functional diversity of lactylation

Lactylation plays a broad and context-dependent regulatory role in cancer biology, with its effects shaped by the nature of the modified protein and the cellular environment in which it occurs (Fig. 1). Among its best-characterized substrates are histones, where lactylation modulates chromatin structure and transcriptional activity [20].

Fig. 1.

Histone lactylation and its role in post-transcriptional RNA regulation. Lactylation plays a central role in modulating the function and localization of RNA-binding proteins (RBPs) by influencing their stability, aggregation status, and interaction with RNA transcripts. In the nucleus, lactylation may affect transcriptional dynamics by altering chromatin accessibility via modified histones and variant histone incorporation. RNA polymerase II (Pol II) activity is coupled with splicing, polyadenylation, and the generation of mature transcripts. These transcripts are associated with the exon junction complex (EJC) and poly(A)-binding proteins (PABPs), which influence translation efficiency and mRNA stability in the cytosol. Upon lactylation-mediated stress adaptation, RBPs may relocalize into stress granules, undergo deadenylation, or trigger decapping mechanisms, leading to translational silencing or mRNA degradation. These processes are also regulated by the cap-binding complex (CBC), eukaryotic initiation factor 4 (EIF4), and the exosome complex, among others. Lactylation of key regulatory nodes-such as decapping enzymes and cytoplasmic processing factors-reinforces feedback circuits that determine whether transcripts are stored, translated, or degraded under metabolic stress conditions

While initial studies identified histone H3 lysine 18 lactylation (H3K18la) as a key mark enriched at promoters of actively transcribed genes, subsequent findings have expanded the landscape considerably [21]. Multiple additional sites-such as H3K9la, H3K14la, H4K12la, and H2BK120la-have since been implicated in tumor progression, particularly in settings of metabolic stress [22–24] (Table 1). For instance, H3K9la has been associated with hypoxia-responsive promoter activation, facilitating transcription of glycolysis-related oncogenes [25]. For example, in esophageal squamous cell carcinoma, hypoxia increases H3K9la levels, which enhances the transcription of LAMC2, a critical factor for cancer cell proliferation and invasion [26]. Similarly, in endothelial cells, H3K9la promotes angiogenesis induced by vascular endothelial growth factor (VEGF), contributing to the formation of pathological neovascularization [27]. Furthermore, in urothelial carcinoma, JMJD1A, a histone demethylase, works in tandem with hypoxia-inducible factor 1α (HIF1α) to promote the expression of glycolysis genes, thereby accelerating cancer cell growth [25].

Table 1.

Summary of known lactylation sites, involved enzymes, and associated microRNAs in cancer-related contexts

Lactylated protein/site	Protein type	Enzyme(s)	Biological function	Associated miRNAs	References(s)
H3K18la	Histone	p300, CBP	Activates transcription at glycolysis-responsive genes	miR-21↑, miR-17–92 cluster↑	[21]
H3K9la	Histone	p300, CBP	Enriched at hypoxia-induced promoters, promotes oncogene expression	miR-155↑, miR-210↑	[25, 26]
H3K14la	Histone	p300	Enhancer-associated, linked to pro-inflammatory gene expression	miR-146a↑	[28]
H3K27la	Histone	p300, CBP	Modulates enhancer dynamics in stress-adaptive gene regulation	(indirect link) miR-34a↓, miR-200c↓	[20]
H4K12la	Histone	p300	Associated with stemness-related gene programs in aggressive tumors	miR-9↑, miR-125b↑	[31]
MOESIN-K72la	Non-histone (cytoskeleton)	Not yet defined	Promotes F-actin binding, cell motility, invasion	Not reported	[20]
PKM2-K62la	Non-histone (metabolic enzyme)	p300	Regulates glycolytic activity, transcriptional co-activation	miR-21↑ (via HIF1α feedforward)	[20]
NBS1 (site unclear)	Non-histone (DNA repair)	Unknown	Enhances DNA repair complex assembly	Possibly linked to miR-182↓	[34]
p53 (site unclear)	Non-histone (transcription factor)	Unknown	Suppresses pro-apoptotic function	miR-34a feedback loop	[36, 37]

This table compiles currently identified lactylation sites on histone and non-histone proteins relevant to tumor progression, metabolic adaptation, and therapy resistance. For each site, the known or putative modifying enzymes (“writers”), biological function, and reported miRNAs that are regulated by or potentially regulate the lactylation event are listed. Upward and downward arrows indicate upregulation and downregulation of miRNAs, respectively. “Site unclear” refers to proteins for which the specific lysine residue of lactylation has not been experimentally determined. Direct and indirect miRNA associations are noted based on published functional or co-expression evidence.

H3K14la, in contrast, is enriched at active enhancers in rapidly proliferating tumour cells and responds dynamically to increased intracellular lactate levels. Studies have shown that H3K14la enhances the production of lactate by boosting the activity of lactate dehydrogenase A (LDHA), thereby promoting the proliferation and metastasis of tumor cells [28]. Furthermore, H3K14la plays a significant role in other types of cancer. For instance, in lung cancer, lncRNA Mir100hg, derived from cancer stem cells (CSC), can increase the production of lactic acid by enhancing the expression of ALDOA, which in turn boosts H3K14la levels [29]. This elevated lactic acid level further promotes the transcription of 169 genes associated with metastasis, ultimately enhancing the metastatic potential of non-CSCs [29]. In hepatocellular carcinoma (HCC), studies have shown that royal jelly acid can inhibit the lactylation of H3K14la and H3K9la, thereby interfering with lactate production and inhibiting tumor invasion and proliferation [30].

H4K12la appears to play a role in supporting transcriptional programs associated with stemness and plasticity, particularly in aggressive cancer subtypes [31]. In ovarian cancer, the lactylation modification of H4K12la is closely linked to the abnormal expression of the RAD23A gene [31]. Specifically, H4K12la activates super enhancers through the MYC transcription factor, enhancing DNA damage repair capabilities and promoting the drug resistance of ovarian cancer cells to niraparib [31]. Furthermore, the lactylation modification of H4K12la is associated with abnormal changes in cancer cell metabolism [31]. Research has shown that in ovarian cancer cells resistant to niraparib, the abnormal activation of glycolysis leads to lactic acid accumulation, which further promotes the lactylation modification of H4K12la [31]. This modification not only affects the gene expression patterns of cancer cells but also enhances their survival and invasiveness by regulating cellular metabolic pathways.

Importantly, lactylation is not restricted to histones [32, 33]. An expanding list of non-histone substrates is now recognized, including proteins involved in genome integrity and cell fate decisions [32, 33]. For example, NBS1-a component of the MRN complex essential for DNA double-strand break repair-undergoes lactylation in a manner that enhances its recruitment to damage sites [34]. Recent studies have highlighted the significance of PTMs, such as lactylation, in modulating the function of NBS1 and its recruitment to damaged DNA sites [34, 35]. Lactylation of NBS1, particularly at lysine 388, has been shown to promote homologous recombination (HR)-mediated DNA repair by facilitating the formation of the MRN complex and the accumulation of HR repair proteins at DSB sites [34]. This modification is crucial for the efficient repair of DNA damage and has implications for chemotherapy resistance in cancer cells, as high levels of NBS1 lactylation correlate with poor patient outcomes in neoadjuvant chemotherapy [34]. Similarly, p53, the canonical tumour suppressor, is lactylated at lysine residues that impair its Pro-apoptotic transcriptional function, enabling tumour cells to better tolerate genotoxic stress [36, 37].

Together, these findings reinforce the view of lactylation as a multifaceted, metabolically encoded regulatory mechanism-one that integrates cellular stress signals into both transcriptional and Post-transcriptional control, with far-reaching consequences for tumour progression and therapeutic resistance.

Spatiotemporal specificity of dynamic lactylation

Lactylation levels and their functional consequences are highly dynamic and influenced by microenvironmental cues. Hypoxia and chemotherapy-induced stress are critical drivers of lactylation dynamics in tumor cells [38]. Under hypoxic conditions, cancer cells depend primarily on glycolysis for energy production, leading to excessive lactate accumulation [39]. This buildup of lactate within the TME amplifies lactylation, modulating gene expression and activating prosurvival signaling pathways [39, 40]. Hypoxia-inducible factors (HIFs) serve as key mediators of this process by upregulating lactylation-associated enzymes, thereby enabling tumor cells to adapt to oxygen-deprived conditions [38].

Chemotherapy profoundly impacts lactylation dynamics by inducing DNA damage and triggering DNA repair pathways in tumor cells [35, 41, 42]. Besides, Chemotherapy-induced stress also plays a significant role in altering lactate dynamics [42, 43]. Chemotherapeutic agents can induce oxidative stress and damage cellular components, increasing glycolytic flux and lactate production as a compensatory mechanism. This metabolic adaptation helps tumor cells survive the cytotoxic effects of chemotherapy and contributes to the development of chemoresistance [41]. Additionally, the interaction between chemotherapy and the TME can lead to the secretion of lactate by cancer-associated fibroblasts, which in turn supports tumor cell survival and resistance to therapy [42].

Additionally, lactic acid accumulation promotes apoptosis resistance in cancer cells via multiple mechanisms, including suppression of Pro-apoptotic regulators such as p53 [44]. Studies have shown that p53 plays a crucial role in cell apoptosis, cell cycle regulation, and DNA repair. However, in many cancers, the function of p53 is often suppressed, leading to increased resistance of cells to apoptosis signals [44].

In a lactic acid environment, the ratio of extracellular lactate to pyruvate increases. This change affects the redox state within cells, thereby regulating their sensitivity to oxidative stress-induced apoptosis [7, 45]. Specifically, a high lactate/pyruvate ratio reduces the NADH/NAD + redox state in the cytoplasm, which inhibits the activation of JNK and Bax, ultimately suppressing the endogenous apoptosis pathway [45]. Emerging evidence has identified FTH1-K48la as a lactylation event that modulates ferroptosis resistance by stabilizing iron sequestration within ferritin complexes, thereby protecting cancer cells from lipid peroxidation–induced death [46, 47].

In conclusion, the dynamic regulation of lactylation in response to hypoxia and chemotherapy-induced stress highlights its contribution to therapy resistance and tumor cell survival.

The role of the miRNA network in metabolic-epigenetic interactions

The interaction between metabolism and epigenetics plays a pivotal role in cancer progression, with miRNAs acting as central mediators of this regulatory network. MiRNAs regulate metabolic processes by targeting metabolic enzymes and epigenetic modifiers, thereby shaping tumor cell plasticity and stress adaptation [10, 11]. Emerging evidence indicates that the relationship between miRNAs and lactylation likely extends beyond isolated roles, establishing a reciprocal regulatory loop that contributes to cancer therapy resistance [11, 43].

While direct evidence linking lactylation and miRNA regulation is still emerging, investigating their interplay offers a promising avenue for understanding metabolic epigenetics in cancer.

miRNA-mediated regulation of key metabolic pathways in cancer

Several miRNAs act as critical regulators of metabolic pathways involved in tumor progression, particularly glycolysis and lactate metabolism [8] (Fig. 2). A well-documented example is the miR-155/LDHA axis, which drives glycolysis and increases lactate output. miR-155 represses tumor suppressors such as C/EBPβ, leading to upregulation of LDHA, a key enzyme catalyzing pyruvate-to-lactate conversion [17, 48]. Elevated LDHA levels reinforce the Warburg effect, supporting tumor growth and establishing a lactate-enriched microenvironment with potential implications for epigenetic remodeling, including histone lactylation [39].

Fig. 2.

miRNA-mediated control of glycolysis, lactylation, and tumor growth. This figure illustrates how lactylation modulates miRNA-dependent immune responses in the tumor microenvironment, with a particular focus on miR-155. In the extracellular space, tumor-derived lactate penetrates immune cell membranes and alters intracellular signaling via lactate-induced post-translational modifications, notably lysine lactylation. Within immune cells, lactylation enhances the transcription of immunomodulatory miRNAs, such as miR-155, which in turn regulate the expression of key DNA repair factors, immune checkpoints, and cytokine-related pathways. Increased miR-155 levels contribute to immune evasion by modulating T-cell differentiation and macrophage polarization. Specifically, lactylation upregulates miR-155 expression, which suppresses pro-inflammatory pathways and enhances tumor-supportive phenotypes in regulatory T cells (Tregs) and M2-like macrophages. Lactylation-dependent feedback loops involving SIRT1 and p300 further sustain this immunosuppressive state, reinforcing tumor immune escape.

Conversely, miR-34a has been shown to negatively regulate SIRT1, an NAD⁺-dependent class III deacetylase that controls histone acetylation and has also been implicated in modulating lactylation through competition for lysine residues and indirect effects on lactate metabolism [49–51]. Inhibition of SIRT1 enhances histone acetylation, which competes with lactylation at specific lysine residues, consequently modulating gene expression. For example, in neuroblastoma, miR-34a inhibits tumor progression by targeting autophagy-related gene 5 (ATG5), suppressing cell proliferation, migration, and autophagy [52]. The miR-34a/SIRT1 axis illustrates a regulatory cross-talk between distinct histone modifications, indicating that miRNAs can potentially shape lactylation dynamics through the regulation of epigenetic enzymes.

miRNA-mediated epigenetic regulation and metabolic plasticity

In addition to their role in metabolic regulation, miRNAs modulate the epigenetic landscape by influencing DNA methylation and histone modifications, thereby shaping the expression of metabolic genes [11, 53, 54].

The miR-29 family, including miR-29a, miR-29b, and miR-29c, directly targets DNA methyltransferase 3A (DNMT3A), a central enzyme regulating DNA methylation [55, 56]. In HCC, the expression of miR-29c-3p is significantly downregulated, while DNMT3B is upregulated [55]. The study found that miR-29c-3p regulates LATS1 methylation by directly targeting DNMT3B, thereby affecting the activity of the Hippo signaling pathway. This mechanism reveals the tumor suppressor role of miR-29c-3p in HCC [55]. Additionally, in prostate cancer, the expression of miR-29 is negatively correlated with DNMT3A expression, suggesting its tumor-suppressive role in cancer [57].

DNMT3A-mediated methylation patterns are closely associated with metabolic gene regulation, and recent findings indicate that these methylation events may potentially influence histone lactylation dynamics. DNMT3A regulates gene expression by adding methyl groups to DNA, and this methylation modification has complex interactions with various forms of histone modifications [58]. Studies have shown that the activity of DNMT3A can be regulated by the modification state of histone H3, for example, the methylation state of H3K4 affects the binding and activity of DNMT3A [59]. Although studies on the direct relationship between DNMT3A and histone lactylation are relatively scarce, existing research has revealed interactions between DNMT3A and other histone modifications. For example, the PWWP domain of DNMT3A can recognize dimethylation and trimethylation of H3K36 in histones, a recognition crucial for the localization and function of DNMT3A in the genome [58, 60].

A key miRNA with epigenetic-metabolic regulatory functions is miR-200c, which governs metabolic reprogramming through the ZEB1/E-cadherin axis [61]. miR-200c represses ZEB1, a transcription factor that drives epithelial-mesenchymal transition (EMT), a process tightly associated with metabolic shifts [62]. ZEB1 downregulation restores E-cadherin expression, promoting a metabolic transition from glycolysis to oxidative phosphorylation [63]. Considering the emerging role of lactylation in EMT regulation, miR-200c-mediated epigenetic modifications may contribute to lactylation dynamics, ultimately influencing cancer cell metabolic adaptation.

Exploring the potential interplay between lactylation and miRNAs

Although the interplay between miRNAs and lactylation remains largely unexplored, a bidirectional regulatory loop may operate, in which lactylation influences miRNA expression while miRNAs reciprocally modulate key lactylation-associated enzymes.

Histone lactylation has been implicated in the regulation of miRNA expression, potentially through its effects on chromatin accessibility [8, 17]. Recent findings suggest that histone lactylation modulates chromatin structure, thereby influencing transcriptional activation [17]. For instance, H3K18la lactylation at the miR-21 promoter is linked to increased miR-21 expression [64, 65]. MiR-21 is widely upregulated in various cancers and plays a crucial role in drug resistance and immune evasion [66]. Studies have shown that miR-21 promotes the survival and proliferation of cancer cells by downregulating tumor suppressor genes such as PTEN and PDCD4, thereby activating the PI3K/Akt signaling pathway [66]. Additionally, overexpression of miR-21 is closely associated with chemotherapy drug resistance to drugs like cisplatin and doxorubicin, which may be achieved through the regulation of FasL expression, a gene involved in apoptosis [67, 68].

In terms of immune evasion, miR-21 promotes tumor growth and angiogenesis by regulating the polarization of tumor-associated macrophages (TAMs) [16, 65]. Studies have found that inhibiting miR-21 expression in TAMs can induce Anti-tumor immune responses, reduce the formation of new blood vessels in tumors, and promote the death of tumor cells [65]. Additionally, miR-21 influences immune evasion mechanisms in the TME by modulating the function of immune cells [64].

miR-21 not only plays a role in tumor cells but also influences the behavior of other cells through exosome-mediated transmission. For example, miR-21 can promote angiogenesis and malignant transformation in lung cancer cells via exosome-mediated transmission [69]. Additionally, high expression of miR-21 in breast cancer is closely associated with drug resistance and cancer progression. By targeting genes such as ABCA1, it affects drug efflux and chemotherapy resistance [70].

Moreover, research has demonstrated that lactic acid can impact the metabolism and immune evasion of tumor cells through various mechanisms, with miRNA playing a crucial role in this process. Firstly, lactic acid can affect the metabolism of tumor cells by regulating the expression of miRNA [17, 71]. For example, lactic acid can activate the E2F pathway, thereby upregulating genes associated with microtubule regulation, thus promoting cell motility and tumor metastasis [72]. Additionally, lactic acid can also inhibit the lactate transporter MCT1 by regulating the expression of miRNA-124, thereby overcoming the drug resistance of breast cancer cells to paclitaxel [73].

Secondly, lactic acid also regulates the proliferation and apoptosis of tumor cells by affecting the expression of miRNA. Studies have found that miRNA-199a-5p can inhibit glycolysis and lactate production in liver cancer cells by targeting hexokinase 2 (HK2), thereby suppressing tumor growth [74]. Additionally, the inhibition of miRNA-155 can enhance the sensitivity of lung cancer cells to radiotherapy by inhibiting glucose metabolism regulated by HK2 [75].

Recent studies have extended this concept by demonstrating that lactate-induced lactylation of non-histone proteins plays a pivotal role in reinforcing immune suppression [76– 78]. Notably, lysine 72 lactylation of the cytoskeletal protein MOESIN enhances its interaction with TGF-β receptor I, subsequently amplifying SMAD3 signaling and stabilizing the immunosuppressive phenotype of Treg cells [76, 77]. This finding establishes a direct mechanistic link between tumor metabolism and immune evasion, whereby lactate functions not only as a metabolic byproduct but also as a Post-translational regulator of membrane-associated immune signaling. Functionally, the inhibition of lactate production disrupts Treg induction and synergizes with Anti-PD-1 therapy in vivo, while reduced MOESIN lactylation levels in Treg cells are associated with improved clinical response in HCC patients [76– 78]. This regulatory mechanism may be achieved by affecting the expression of miRNA, further enhancing the tumor’s ability to evade the immune system.

In turn, miRNAs regulate lactylation by targeting enzymes involved in lactylation regulation. miRNAs that modulate TIP60, an established lactyltransferase, may regulate both the levels and specificity of lactylation [19]. Similarly, miRNAs targeting histone deacetylases (HDACs), such as HDAC3, which is involved in lactyl group removal, may contribute to the dynamic regulation of lactylation [79, 80].

These findings indicate that miRNAs are not merely responsive to lactylation but actively modulate its dynamics, establishing a regulatory loop that integrates metabolic and epigenetic reprogramming in tumors (Fig. 3).

Fig. 3.

Intersection of lactylation and miRNA regulation in cancer progression. This schematic summarizes the converging mechanisms by which lactylation and microRNAs (miRNAs) cooperatively facilitate therapy resistance in cancer. Lactylation of histone H3 at lysine 18 (H3K18la) and DNA repair proteins such as BRCA1 and MRE11 enhances homologous recombination repair efficiency, thereby contributing to chemoresistance. Concurrently, miRNAs such as miR-182 and miR-34a modulate this process by targeting BRCA1 and anti-apoptotic genes (e.g., BCL-2), respectively. At the immunological level, lactylation upregulates PD-L1 expression and promotes immunosuppressive signaling. miRNAs such as miR-15a/16 and miR-1246 further modulate immune evasion by targeting PD-L1 and enhancing M2 macrophage polarization. Lactylation also reprograms cellular metabolism by facilitating glycolysis and tricarboxylic acid (TCA) cycle adaptation under hypoxia, often in conjunction with miR-155 and miR-34a. At the epigenetic level, lactylation increases chromatin accessibility, while miR-29b and miR-148a regulate DNA and histone methylation states, contributing to long-term transcriptional adaptation. Cancer types represented include breast, lung, colorectal, and melanoma, underscoring the widespread relevance of lactylation–miRNA crosstalk across malignancies

Lactylation-driven cancer therapy resistance via miRNA network regulation

Cancer therapy resistance remains a critical challenge, limiting the long-term efficacy of chemotherapy, radiotherapy, and targeted therapies. While lactylation has garnered increasing interest in epigenetic regulation and metabolic reprogramming, its role in therapy resistance is still being actively explored. Recent studies indicate that lactylation may influence miRNA networks involved in DNA repair, metabolic adaptation, and immune evasion’s key mechanisms contributing to therapy resistance. Although the mechanistic connections between lactylation and miRNA regulation in this context are not yet fully understood, investigating these interactions could uncover potential therapeutic targets.

Dual regulation of DNA repair pathways

The efficiency of DNA damage repair critically influences the sensitivity of cancer cells to genotoxic therapies such as chemotherapy and radiotherapy [81, 82]. Lactylation has been implicated in regulating the function of DNA repair proteins, particularly within the HR pathway [8, 9, 17]. HR is essential for repairing double-strand breaks (DSBs) [83, 84]. Emerging evidence indicates that lactylation enhances the stability and activity of HR proteins, which may enhance DNA repair efficiency and contribute to therapy resistance [83]. First, Meiotic recombination 11 homolog A (MRE11) is a key protein in HR repair. Its lactylation can enhance its binding to DNA, thereby improving the ability to cut and repair DNA ends [84]. This lactylation is mediated by CBP acetyltransferase and depends on ATM′s phosphorylation of MRE11 [84]. By inhibiting CBP or LDH, the lactylation level of MRE11 can be reduced, thus weakening HR repair capabilities and increasing the sensitivity of tumor cells to chemotherapy drugs [84].

In addition, the lactylation of NBS1 is crucial for DNA repair and chemotherapy resistance [85]. The lactylation of NBS1 at the K388 site is a key step in the formation of the MRE11-RAD50-NBS1 (MRN) complex, promoting the accumulation of HR repair proteins at DNA double-strand break sites [85]. TIP60 has been identified as the lactyltransferase responsible for lactylating NBS1, while HDAC3 serves as the delactylase, removing the lactyl group from NBS1 and thereby reversing this PTM [19]. High levels of NBS1 K388 lactylation are associated with poor chemotherapy outcomes; reducing lactate production can inhibit this lactylation, thereby decreasing DNA repair efficiency and overcoming chemotherapy resistance [85].

In the case of BRCA1, lactylation may also regulate its function by affecting its interactions with other repair proteins [86]. BRCA1 plays a crucial role in HR repair, and its functional regulation is essential for maintaining genomic stability [86]. Studies have shown that the function of BRCA1 depends not only on its activity but also on its localization in the nucleus and interactions with other proteins [87].

miRNA-mediated regulation of DNA repair adds another dimension to the control of genomic stability. miR-182 directly targets BRCA1, suppressing its expression and sensitizing cells to PARP inhibitors, which leverage HR deficiency to induce cytotoxicity in cancer cells [88]. Lactylation-driven HR activation may counteract miR-182-mediated BRCA1 suppression, potentially enabling cancer cells to evade PARP inhibitor-induced synthetic lethality [89, 90]. Investigating the interplay between lactylation and miRNAs in DNA repair regulation may reveal therapeutic strategies to overcome resistance mechanisms to DNA-damaging treatments.

Metabolic adaptations in chemotherapy resistance

Metabolic reprogramming is a key feature of cancer cells under therapeutic stress, facilitating apoptotic evasion and prolonged survival [91]. Lactylation plays a role in this adaptation by modulating key metabolic regulators, including HIF-1α, a central regulator of hypoxia-driven transcription [92]. The HIF-1α/miR-210 axis sustains CSC properties, which contribute to chemotherapy resistance [93, 94]. Since lactylation is associated with HIF-1α stabilization, it may enhance miR-210 expression, thereby promoting a metabolic profile that sustains CSC properties and therapy resistance [93–95].

Lactic acid plays a crucial role in cellular metabolism, especially under oxidative stress conditions [96]. Studies have shown that lactic acid can influence the cell’s antioxidant capacity through multiple pathways [40, 96]. First, lactic acid enhances the cell’s antioxidant ability by regulating the synthesis pathway of glutathione (GSH) [97]. GSH is an important intracellular antioxidant that effectively eliminates reactive oxygen species (ROS), protecting cells from oxidative damage [98]. In certain situations, the accumulation of lactic acid may promote GSH synthesis by affecting cellular metabolic pathways [99]. For example, lactic acid can indirectly regulate the NAD+/NADH ratio by influencing the activity of LDH, thereby affecting GSH synthesis [99]. Additionally, lactic acid may enhance cellular antioxidant capacity by regulating the expression of enzymes related to GSH synthesis, such as glutamine synthetase and glutamate-cysteine ligase [100].

Importantly, recent findings have highlighted a non-enzymatic lactylation pathway involving the glyoxalase system. Glo1, a key enzyme in the glucosidase system, is responsible for detoxifying methylglyoxal (MG). MG, a highly reactive α-dicarbonyl compound, is primarily produced through the glucose degradation pathway. It reacts non-enzymatically with arginine residues in proteins to form advanced glycation end products (AGEs), which are associated with various metabolic diseases [101]. Under the influence of Glo1, MG binds with GSH to form LGSH. This compound is then hydrolyzed by Glo2 (glycosyl oxidase 2) to produce D-lactic acid and regenerate GSH. Research indicates that LGSH not only aids in the detoxification of MG but also transfers the lactate group to the lysine residues of proteins through a non-enzymatic S-to-N acylation transfer reaction, resulting in LactoylLys modification. This modification is enriched in glycolytic enzymes and may regulate glycolysis flux under conditions of hyperglycemia or the Warburg effect [102, 103]. Moreover, LGSH plays a crucial role in inflammatory signaling pathways. Studies have shown that in the absence of Glo2, the levels of LGSH and histone lactylation within cells significantly increase, leading to an enhanced inflammatory response. This suggests that LGSH is not only a key driver of histone lactylation but also a significant contributor to inflammatory signaling pathways [103]. This Glo1-LGSH-mediated lactylation expands the repertoire of lactylation events beyond the canonical p300-dependent pathway and may further link redox homeostasis with epigenetic regulation in metabolically stressed tumor cells.

In cancer cells, the metabolic reprogramming of lactic acid is also closely related to the synthesis of GSH. Studies have found that the accumulation of lactic acid in cancer cells can enhance GSH synthesis by regulating metabolic pathways, thereby improving the cell′s tolerance to oxidative stress [91]. Additionally, lactic acid may indirectly promote the synthesis and accumulation of GSH by affecting cellular energy metabolism [104].

In summary, lactic acid plays a complex and crucial role in cellular antioxidant stress [97, 104, 105]. By regulating the synthesis pathway of GSH, lactic acid can enhance the cell′s antioxidant capacity, helping cells resist damage caused by oxidative stress [105].

While the regulatory role of miRNAs in redox balance has been extensively studied and recognized. Studies have shown that miRNAs can participate in the regulation of redox balance through various mechanisms. For example, in the pathophysiology of cardiac hypertrophy, specific oxidative modifications at miR-1 sites have been found to influence cardiac hypertrophy by regulating other mRNAs, indicating that the oxidative modification of miRNAs plays a significant role in redox-mediated gene expression [106].

In cancer research, the disruption of redox balance is considered one of the key factors in the onset and progression of cancer [107, 108]. Studies have found that iASPP reduces ROS levels by competing with Nrf2 for Keap1 binding, thereby promoting cancer growth and drug resistance, further highlighting the importance of redox balance in cancer [108].

In the genomic stability and stress response of plants, redox balance forms a complex network with DNA damage response (DDR) and miRNAs. miRNAs can regulate the redox system and DDR pathway at the Post-transcriptional level, thereby maintaining genomic stability under adverse conditions [109, 110].

The role of miRNAs in lactylation-driven metabolic adaptations is not yet fully understood. However, as miRNAs are known regulators of redox balance, their interaction with lactylation in chemotherapy resistance warrants further exploration.

Immune evasion and therapy resistance

The immunosuppressive TME is a key driver of cancer progression and therapy resistance [1, 15]. Lactylation is suggested to regulate immune checkpoint pathways, especially by driving T cell exhaustion [15, 111, 112]. This regulation may occur through miRNA-mediated control of immune checkpoint regulators like PD-1 and CTLA-4 [112]. miR-155a, for instance, directly targets these molecules, thereby shaping T-cell responses within the TME [70, 113, 114]. Lactylation-driven suppression of miR-155a via chromatin remodeling may contribute to sustained immune checkpoint activation, thereby weakening T cell-mediated antitumor responses and limiting the effectiveness of immune checkpoint blockade therapies [113–115] (Fig. 4).

Fig. 4.

miR-155 and miR-34a coordinate immune escape via PD-1/PD-L1 axis in the tumor microenvironment. This schematic depicts how tumor-derived metabolic and epigenetic cues reshape the immune landscape via microRNA-mediated mechanisms. Under hypoxic and lactate-enriched conditions, elevated miR-155 expression promotes PD-L1 upregulation in tumor cells and antigen-presenting cells, dampening T cell cytotoxicity. Concurrently, the downregulation of tumor-suppressive miR-34a-partially mediated by histone lactylation-removes post-transcriptional repression on PD-L1, reinforcing immune escape. Together, miR-155 and miR-34a establish a synergistic regulatory axis that enhances PD-1/PD-L1 signaling and contributes to the immunosuppressive TME.

Furthermore, Lactic acid accumulates in the tissue microenvironment of chronic inflammation and cancer, affecting the function of immune cells [116, 117]. In the context of chronic inflammation, the accumulation of lactic acid promotes metabolic remodeling of CD4 + T cells, leading to changes in their effector phenotype and increased production of IL-17 via the nuclear PKM2/STAT3 pathway [117]. Additionally, lactic acid reduces glycolysis by enhancing fatty acid synthesis, causing CD4 + T cells to remain in inflamed tissues [117].

In macrophages, lactylation affects their polarization state by regulating the expression of miR-155 [118, 119]. Studies show that miR-155 plays a crucial role in the polarization process of macrophages. The upregulation of miR-155 is associated with M1-type macrophages, while its suppression promotes the polarization of M2-type macrophages [118]. In heart injury, exosomes secreted by macrophages containing miR-155 can inhibit fibroblast proliferation and promote inflammatory responses [119].

In addition, miR-155 is also induced during viral infection and is associated with an enhanced antiviral immune response [120]. Studies have found that in viral respiratory infections of young children, the secretion of miR-155 from airways is linked to enhanced TH1 polarization and an antiviral immune response [120]. In HCC associated with hepatitis, miR-155 promotes malignant progression by influencing the polarization of TAMs [121].

In obesity-related metabolic inflammation, exosomal miR-34a secreted by adipocytes promotes fat tissue inflammation caused by obesity by inhibiting the polarization of M2 macrophages [116]. In alcoholic liver disease, butyrate regulates the HDAC1/miR-155 axis to suppress inflammation and promote macrophage polarization, thereby alleviating inflammation [122].

In conclusion, lactylation affects the polarization state of macrophages by regulating the expression and function of miR-155 and plays an important role in a variety of diseases. This provides potential targets for the development of new therapeutic strategies.

Clinical translation and therapeutic strategies

With growing insights into lactylation and miRNA regulation in cancer therapy resistance, a key priority is to evaluate their clinical applicability. Lactylation-related markers and miRNA profiles could serve as valuable tools for biomarker discovery, dynamic tracking of treatment efficacy, and the development of targeted therapies. Although lactylation is an emerging field, its interplay with miRNA regulation could unveil novel therapeutic strategies, with potential applications in combating drug resistance and optimizing immunotherapy outcomes.

Targeting the metabolic-epigenetic axis: emerging therapeutic strategies

As metabolic-epigenetic interactions gain increasing attention in cancer therapy resistance, targeting lactylation and miRNA pathways has emerged as a promising therapeutic avenue [123, 124]. A rational approach is to combine lactylation inhibitors with miRNA-targeted therapies [125]. LDHA inhibitors, such as FX11, show preclinical potential for reducing lactate production and interfering with lactylation-mediated metabolic shifts [126–128]. When used alongside miRNA mimics or antagonists, these inhibitors could potentiate treatment efficacy through dual targeting of metabolic and epigenetic resistance mechanisms.

Additionally, advances in nanoparticle-based drug delivery systems are accelerating the clinical development of miRNA therapeutics [129] (Fig. 5). Nanocarriers, such as liposomal formulations, are engineered to deliver miRNA mimics (e.g., miR-34a) to tumor cells, enhancing miRNA stability, bioavailability, and tumor targeting [50, 52, 130]. Preclinical studies indicate that liposomal miR-34a delivery suppresses tumor growth and enhances chemotherapy sensitivity [50, 131]. These nanomedicine-based strategies offer a promising approach to circumventing drug resistance and refining therapeutic precision through targeted metabolic and gene expression modulation.

Fig. 5.

Nanoparticle-mediated miRNA delivery for tumor therapy. This diagram illustrates a self-reinforcing regulatory loop by which lactate accumulation and subsequent lysine lactylation (Kla) reshape the epigenetic landscape of tumor cells, thereby enhancing therapy resistance. Elevated intracellular lactate-produced through aerobic glycolysis-induces lactylation of histone and non-histone proteins (e.g., H3K18la, MRE11la), leading to the transcriptional upregulation of oncogenic microRNAs such as miR-21 and the miR-17~92 cluster. These miRNAs, in turn, suppress lactylation erasers (e.g., HDAC1/3) and promote expression of glycolytic enzymes (e.g., LDHA, PKM2), resulting in sustained lactate production and Kla activity. This feedforward loop supports DNA repair activation, apoptosis inhibition, and survival of therapy-stressed cells

Future directions and challenges

While targeting the lactylation-miRNA axis offers a promising avenue in cancer therapy, several critical challenges persist. First, lactic acid plays a crucial role in the TME; it is not only a byproduct of cancer cell metabolism but also participates in immune suppression, affecting Anti-tumor immune responses [132]. Therefore, strategies targeting lactate metabolism need to overcome the complexity of the TME to ensure effective treatment.

Secondly, the role of miRNAs in cancer is complex and diverse; they can function as oncogenes or tumor suppressors [133]. Therefore, developing treatments targeting specific miRNAs requires precise identification of their specific functions in different types of cancer. Moreover, the delivery of miRNAs remains a major challenge. Although various delivery systems, such as nanoparticles and cell-penetrating peptides have been developed, further research is needed to ensure the stability and specific delivery of miRNAs in vivo [134, 135].

In addition, the interaction between miRNA and lactic acid metabolism also requires further research. Lactic acid not only affects the metabolic pathways of cancer cells but also influences cancer progression by regulating miRNA expression [136]. Therefore, understanding the complex relationship between lactic acid and miRNA is crucial for developing effective therapeutic strategies.

Moreover, a major translational challenge arises from the extensive molecular overlap between lactylation and acetylation [137]. Both modifications share key enzymatic machinery, such as writers (e.g., p300) and erasers (e.g., HDACs, SIRT1), making it difficult to achieve pathway-specific inhibition without off-target effects [138–140]. This biochemical convergence raises concerns regarding therapeutic selectivity, as efforts to inhibit lactylation may inadvertently alter acetylation patterns with broad and unpredictable consequences on gene regulation.

Hence, before advancing lactylation-targeted therapies into clinical validation, it is imperative to delineate the distinct functional roles of these PTMs and to develop precision tools–such as site-specific inhibitors or engineered enzymes-that can discriminate between acetylation and lactylation with minimal cross-reactivity [141].

Finally, clinical translation is a significant challenge. Despite some progress in laboratory studies, applying these findings to clinical treatment still requires overcoming many obstacles, including drug safety, efficacy, and patient-individual differences [142]. Therefore, future research needs to focus on optimizing miRNA delivery systems, gaining deeper insights into the interaction between lactic acid and miRNA, and conducting more clinical trials to validate its therapeutic potential.

Conclusion

The interplay between lactylation and miRNAs forms a pivotal regulatory network in metabolic-epigenetic crosstalk, shaping cancer progression and therapy resistance. While lactylation is increasingly recognized as a key PTM that influences chromatin accessibility, gene expression, and protein function, miRNAs function as central epigenetic regulators of metabolic and signaling pathways. Although the precise mechanistic link between lactylation and miRNAs is not yet fully understood, emerging data indicate that their interplay may drive metabolic adaptations, modulate DNA repair processes, and facilitate immune evasion-three key mechanisms of therapy resistance.

Given these insights, targeting the lactylation-miRNA axis emerges as a viable strategy for circumventing drug resistance and enhancing therapeutic efficacy. Pharmacological inhibition of lactylation-modulating enzymes (e.g., LDHA inhibitors) in combination with miRNA-based therapeutics (e.g., miRNA mimics or antagonists) presents an opportunity to modulate tumor metabolism and enhance therapy sensitivity. Moreover, biomarker discovery based on lactylation signatures (e.g., H3K18la IHC) and circulating miRNAs (e.g., miR-21, miR-155) could advance precision oncology through dynamic monitoring of treatment efficacy and disease trajectory.

Despite these promising prospects, critical challenges persist. A deeper understanding of the spatiotemporal dynamics of lactylation and miRNA regulation is essential for elucidating how these modifications operate within diverse tumor types and microenvironmental contexts. Future research must further investigate the context-dependent effects of lactylation on miRNA networks, with a specific focus on DNA damage repair, metabolic reprogramming, and immune regulation. Advanced multi-omics approaches, single-cell sequencing, and in vivo models are indispensable for unraveling the functional relevance of lactylation-miRNA interactions and pinpointing viable therapeutic targets.

In summary, although research in this area remains nascent, investigating the lactylation-miRNA axis offers new insights into cancer pathophysiology. By dissecting the mechanistic intricacies of this interaction, future studies could drive the development of novel therapeutic strategies targeting metabolic-epigenetic interactions to enhance treatment efficacy in therapy-resistant cancers.

Abbreviations

PTM

Post-translational modification

TME

Tumor microenvironment

HIFs

Hypoxia-inducible factors

ATG5

Autophagy-related gene 5

DNMT3A

DNA methyltransferase 3A

HCC

Hepatocellular carcinoma

EMT

Epithelial-mesenchymal transition

TAMs

Tumor-associated macrophages

HK2

Hexokinase 2

HDACs

Histone deacetylases

HR

Homologous recombination

DSBs

Double-strand breaks

LDH

Lactate dehydrogenase

MRN

MRE11-RAD50-NBS1

CSC

Cancer stem cell

GSH

Glutathione

ROS

Reactive oxygen species

DDR

DNA damage response

RBP

RNA-binding protein

UTR

Untranslated region

Pol II

RNA polymerase II

PABP

Poly(A)-binding protein

EJC

Exon junction complex

CBC

Cap-binding complex

EIF4

Eukaryotic initiation factor 4

Treg

Regulatory T cell

miRNA

MicroRNA

miR-155

MicroRNA-155

miR-34a

MicroRNA-34a

SIRT1

Sirtuin 1, a NAD⁺-dependent deacetylase

p300

Histone acetyltransferase p300

H3K18la

Histone H3 lysine 18 lactylation

HR

Homologous recombination

PD-L1

Programmed death-ligand 1

LDHA

Lactate dehydrogenase A

TCA

Tricarboxylic acid cycle

BCL-2

B-cell lymphoma 2

DNMT3A

DNA methyltransferase 3A

PD-1

Programmed cell death protein 1

PD-L

Programmed death-ligand 1

LDHA

Lactate dehydrogenase A

PKM2

Pyruvate kinase M2 isoform

MRE11

Meiotic recombination 11 homolog A

Author contributions

All authors listed have made substantial, direct, and intellectual contributions to the work and have approved it for publication.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82203377 to Yanwei Lu; 82473238 to Haibo Zhang), Zhejiang natural science foundation of China (Grant number: LY24H160022 to Haibo Zhang). Zhejiang Health Science and Technology Project (2025KY031 to Haibo Zhang).

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

Not applicable.