Lactylation in pancreatic cancer: From molecular mechanisms to therapeutic perspectives

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterized by intense metabolic reprogramming and an immunosuppressive tumor microenvironment. The recent discovery of lactylation, a novel post-translational modification derived from lactate, provides a direct molecular link between glycolysis and the regulation of gene expression. This review synthesizes the emerging role of lactylation in PDAC pathogenesis. We detail how a lactate-rich microenvironment fuels the lactylation of histones and non-histone proteins, driving oncogenic processes such as transcriptional reprogramming, maintenance of lineage plasticity, and therapeutic resistance. Furthermore, lactylation in stromal and immune cells reinforces immunosuppression, facilitating tumor progression. We critically evaluate the translational potential of targeting this axis through inhibitors of lactate production, transport, or the epigenetic writers themselves. While promising, these strategies face significant challenges, including achieving molecular specificity and overcoming drug delivery barriers in PDAC. We conclude that lactylation represents a critical metabolic-epigenetic link in PDAC and a compelling therapeutic target worthy of further investigation.

Key Words: Lactylation; Epigenetic; Metabolic reprogramming; Lactate; Pancreatic ductal adenocarcinoma; Tumor microenvironment

Core Tip: This mini-review highlights lactylation, a lactate-derived epigenetic modification, as a pivotal mechanism linking the intense glycolytic metabolism of pancreatic ductal adenocarcinoma to its aggressive phenotype. We synthesize how lactylation of histones and non-histone proteins drives oncogenic transcription, chemoresistance, and immune suppression. The article critically evaluates the promise of targeting lactylation “writers” and “erasers”, lactate transporters, and metabolic enzymes for therapy, while also discussing the challenges of specificity, drug delivery, and biomarker validation that must be addressed to translate these strategies to the clinic.

INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a 5-year survival rate of approximately 13%, largely due to late diagnosis, aggressive biology, and profound therapeutic resistance[1,2]. Current standard-of-care therapies, including chemotherapy and radiotherapy, offer limited survival benefit, highlighting an urgent, unmet clinical need for novel therapeutic targets[3]. The metabolic peculiarities of PDAC notably its intense glycolytic flux and lactate-rich microenvironment represent one such vulnerability[4]. PDAC is characterized by profound metabolic reprogramming, particularly the Warburg effect, which leads to excessive lactate production. Once considered a metabolic waste product, lactate is now recognized as a signaling molecule and precursor for lactylation a lysine modification linking metabolism to epigenetic regulation. Since its discovery in 2019[5], lactylation has been implicated in immune modulation, gene expression, and cancer progression. In PDAC, lactylation is emerging as a central driver of oncogenesis and immunosuppression. This mini-review explores how lactylation, a novel lactate-derived epigenetic modification, bridges this metabolic reprogramming to the aggressive phenotype of PDAC. We synthesize the molecular mechanisms of lactylation, its specific roles in PDAC pathogenesis and therapy resistance, and evaluate the translational potential of targeting this axis, while also acknowledging current limitations and future challenges.

WHAT IS LACTYLATION

Lactylation is the covalent addition of a lactyl group to the ε-amino group of lysine residues on histones and non-histone proteins[5]. First identified on histone H3K18, the modification is catalysed enzymatically by histone acetyltransferases that can use lactyl-coenzyme A (CoA) as an alternative acyl-donor[6]. Lactyl-CoA itself is generated from lactate via the sequential action of lactate dehydrogenase A (LDHA) and acyl-CoA synthetase short-chain family member 2[7]. This process is highly regulated; lactyl-CoA synthesis is induced under specific pathophysiological conditions common in PDAC, such as hypoxia and nutrient stress, which drive high glycolytic flux and lactate production[7,8]. Furthermore, subcellular compartmentalization is critical, with nuclear-localized acyl-CoA synthetase short-chain family member 2 playing a key role in generating the lactyl-CoA pool used for histone modification[7]. Because intratumoural lactate concentrations can exceed 20 mmol/L, lactylation constitutes a direct metabolic epigenetic relay[9]. Mass-spectrometry surveys have now mapped > 2000 lactylated lysines across the proteome, indicating broad regulatory scope[10].

The lactylation landscape is dynamically regulated by writers, readers, and erasers. While P300/CBP are established writers, the identification of specific reader proteins that selectively bind lactylation marks is an area of active investigation, though it is hypothesized that bromodomains, which recognize acetyl-lysine, may have some affinity[11]. Importantly, lactylation is a reversible modification. Recent studies have identified several erasers, including certain class I histone deacetylases (HDAC1-3) and sirtuins (SIRTs), with SIRT2 and SIRT3 showing robust delactylase activity[6,12]. The tissue-specific expression and activity of these erasers in PDAC and their therapeutic potential relative to targeting writers remain to be fully elucidated (Figure 1).

Figure 1 Schematic of lactylation from lactate production to epigenetic and functional consequences. CoA: Coenzyme A; LDHA: Lactate dehydrogenase A.

LACTYLATION IN CANCER: LESSONS FROM OTHER MALIGNANCIES

The functional roles of lactylation, first characterized in other cancers, provide a critical context for understanding its potential impact in PDAC. The mechanisms described below, while not yet fully validated in PDAC, highlight conserved pathways that are likely relevant given the shared features of metabolic dysregulation across cancers.

Transcriptional reprogramming

Global chromatin immunoprecipitation sequencing (ChIP-seq) shows that H3K18 La localises to active enhancers and promoters, frequently overlapping with H3K27ac but also marking a unique set of genes enriched for glycolysis and hypoxia response[5]. In breast cancer, H3K18 La drives MYC and vascular endothelial growth factor A expression, promoting angiogenesis and proliferation[13]. Given the critical role of MYC and angiogenesis in PDAC, this mechanism is likely to be highly relevant and warrants direct investigation. In hepatocellular carcinoma, lactylation of H3K9 activates programmed death 1 transcription, fostering immune evasion[14].

Immune evasion

Tumour-derived lactate accumulates in the extracellular space, inhibiting T-cell function and simultaneously inducing lactylation of programmed death 1 and interleukin-10 loci in tumour-associated macrophages, thereby reinforcing an immunosuppressive loop[15]. This establishes a paradigm for metabolic regulation of immunity that is directly applicable to the intensely immunosuppressive PDAC microenvironment.

Metabolic feedback

Lactylation of pyruvate kinase M2 at K62 inhibits its activity, diverting glycolytic flux toward the pentose-phosphate pathway and nucleotide biosynthesis an adaptation observed in colorectal cancer[16]. While this specific modification has not been reported in PDAC, the profound glycolytic dependency of PDAC cells suggests that similar metabolic feedback loops via lactylation are probable and represent a promising area for future research.

MECHANISM OF LACTYLATION IN PANCREATIC CANCER

Lactate-rich microenvironment of PDAC

PDAC displays the highest glycolytic rate among solid tumours, driven by mutant KRAS-MAPK signalling that up-regulates LDHA and monocarboxylate transporter (MCT4)[17]. Spatial metabolomics reveals intratumoural lactate levels > 30 mmol/L, creating a niche permissive for extensive lactylation[18].

Histone lactylation and lineage plasticity

Single-cell CUT and Tag profiling of patient-derived organoids identified H3K18 La peaks at pancreatic progenitor genes (PDX1, MNX1) and dedifferentiation markers (Sox9, Krt19)[19]. Genetic ablation of P300/CBP or pharmacological inhibition by A-485 reduced H3K18 La, restored acinar differentiation, and impaired tumour engraftment. While these studies suggest a causal role for lactylation in maintaining PDAC lineage plasticity, it is important to note that P300/CBP are broad-specificity writers for both acetylation and lactylation. Therefore, the phenotypic changes observed upon their inhibition cannot be attributed solely to reduced lactylation. More direct evidence, perhaps using lactylation-specific blocking antibodies or engineered writer mutants, is needed to establish strict causality and avoid overinterpretation.

Non-histone lactylation and therapeutic resistance

Mass-spectrometry screens uncovered lactylation of DNA-repair proteins breast cancer type 1 susceptibility protein (K1402) and RAD51 (K70) in gemcitabine-resistant PDAC cells[20]. Lactylation enhanced their DNA-binding affinity, accelerated homologous-recombination repair, and blunted gemcitabine efficacy. Conversely, LDHA inhibition by FX11 or MCT1 blockade with AZD3965 reduced lactyl-CoA, decreased RAD51 lactylation, and re-sensitized tumours to chemotherapy in KPC mouse models.

Tumour-stroma lactylation cross-talk

Cancer-associated fibroblasts secrete lactate via MCT4; uptake by tumour cells through MCT1 fuels nuclear lactyl-CoA synthesis[21]. Dual MCT1/4 inhibitor syrosingopine[22] lowered global lactylation, reduced myeloid-derived suppressor cell infiltration, and synergised with anti-programmed cell death protein 1 therapy (Table 1, Figure 2)[13,14,16,19,20,23-25].

Figure 2 Lactylation drives pancreatic cancer progression through multiple mechanisms. A: Lineage plasticity; B: Therapeutic resistance; C: Tumor stroma. BRCA1: Breast cancer type 1 susceptibility protein; CoA: Coenzyme A; LDHA: Lactate dehydrogenase A; MCT: Monocarboxylate transporter; MDSC: Myeloid-derived suppressor cells; PDAC: Pancreatic ductal adenocarcinoma; PD-1: Programmed death 1.

Table 1 Key lactylation sites and their functional roles in cancer.

Lactylated substrate	Cancer type	Functional consequence	Ref.
Histone H3K18	PDAC, breast cancer	Drives expression of MYC, vascular endothelial growth factor A, and pancreatic progenitor genes (PDX1, MNX1); promotes lineage plasticity	Yang et al[13], Lee et al[19], Wang et al[23]
Histone H3K9	Hepatocellular carcinoma	Activates programmed death 1 transcription, fostering immune evasion	Liu et al[14], Li et al[24]
PKM2	Colorectal cancer	Inhibits PKM2 activity, diverting glycolytic flux toward the pentose-phosphate pathway	Chen et al[16]
Breast cancer type 1 susceptibility protein (K1402)	PDAC (gemcitabine-resistant)	Enhances DNA-binding affinity, accelerates HR repair, promoting chemoresistance	Wang et al[20], Li et al[25]
RAD51 (K70)	PDAC (gemcitabine-resistant)	Enhances DNA-binding affinity, accelerates HR repair, promoting chemoresistance	Wang et al[20], Li et al[25]

It summarizes significant lactylation targets, their associated cancer contexts, and the functional consequences discussed above. HR: Homologous-recombination; PDAC: Pancreatic ductal adenocarcinoma; PKM2: Pyruvate kinase M2.

FUTURE PERSPECTIVES AND APPLICATIONS

Precision mapping and biomarker development

Development of lactyl-CoA-sensitive Forster resonance energy transfer reporters and genome-wide lactylome CRISPR screens will identify context-specific lactylation nodes amenable to intervention[26]. Liquid-biopsy detection of lactylated histones in circulating tumour DNA (ctDNA) correlates with high tumour burden and poor response to therapy[27], offering a non-invasive stratification tool. However, significant challenges remain. The sensitivity and specificity of detecting lactylated histones in ctDNA are not yet fully established, and it is unclear how these protein marks survive plasma nuclease degradation. The technological platform (e.g., mass spectrometry vs immunoassays) requires standardization. Furthermore, the clinical utility of lactylated ctDNA must be validated against established PDAC biomarkers like carbohydrate antigen 19-9 in large, prospective cohorts, accounting for cost and accessibility.

Therapeutic strategies and translational challenges

Table 2 summarizes the various inhibitors and combination strategies targeting the lactylation axis. However, the optimistic view of these strategies must be tempered by a discussion of the significant challenges in translation. These include: (1) Achieving specificity when targeting writers like P300/CBP or erasers like SIRT2, which regulate multiple modifications; (2) The potential for metabolic compensation and toxicity when inhibiting central enzymes like LDHA; (3) The difficulty in drug delivery to the dense, fibrotic PDAC stroma; and (4) Identifying predictive biomarkers to select patients most likely to benefit from these approaches. Combining LDHA inhibitors with bromodomain and extra-terminal bromodomain blockers prevents compensatory H3K27ac increase, sustaining epigenetic suppression of MYC and breast cancer type 1 susceptibility protein[28]. Early-phase trials (NCT06093452) are testing safety of the LDHA inhibitor NDI-091143 with nab-paclitaxel/gemcitabine backbone (Table 2, Figure 3).

Figure 3 Therapeutic targeting strategies for lactylation in pancreatic ductal adenocarcinoma. ACSS2: Acyl-CoA synthetase short-chain family member 2; BET: Bromodomain and extra-terminal; CoA: Coenzyme A; LDHA: Lactate dehydrogenase A; MCT: Monocarboxylate transporter; PD-1: Programmed death 1.

Table 2 Emerging therapeutic agents, tools, and biomarkers targeting the lactylation axis.

Category	Agent/tool	Molecular target/method	Observed effect/application	Development stage	Key challenges
Therapeutic agent	A-485	P300/CBP (Writer)	Reduces H3K18 La, restores acinar differentiation, impairs tumor growth	Preclinical	Lack of specificity (inhibits acetylation); potential toxicity
Therapeutic agent	FX11	LDHA	Reduces lactyl-CoA, decreases RAD51 lactylation, re-sensitizes to gemcitabine	Preclinical	Metabolic compensation; system toxicity
Therapeutic agent	Syrosingopine	MCT1/4	locks lactate transport, lowers global lactylation, reduces myeloid-derived suppressor cell infiltration, and synergizes with anti- programmed cell death protein 1	Preclinical	Off-target effects; delivery to tumor site
Therapeutic agent	AZD3965	MCT1	Blocks lactate uptake, reduces lactylation, re-sensitizes to chemotherapy	Early-phase trial	Dose-limiting toxicity (acidosis); expression of alternative transporters
Therapeutic agent	NDI-091143	LDHA	Inhibits lactate production; tested in combination with nab-paclitaxel/gemcitabine	Early-phase trial (NCT06093452)	Efficacy and safety in humans unknown
Therapeutic agent	Engineered hydrolase	Lactyl-CoA	Selectively depletes nuclear lactyl-CoA, attenuating tumor growth	Preclinical	Delivery and immunogenecity of bacterial enzyme
Research tool	Genome-wide lactylome CRISPR screens	N/A	Identify context-specific lactylation nodes for intervention	Research tool	Functional validation required
Research tool	Lactyl-CoA-sensitive Forster resonance energy transfer reporters	N/A	Real-time measurement of nuclear lactyl-CoA dynamics	Research tool	Technical implementation in vivo
Biomarker	Liquid biopsy for lactylated histones in circulating tumour DNA	Mass spectrometry/immunoassay	Non-invasive patient stratification; correlates with tumor burden and poor response	Research/development	Sensitivity/specificity; standardization; clinical validation

It summarizes the various inhibitors and combination strategies targeting the lactylation axis. Lactyl-CoA: Lactyl-coenzyme A; LDHA: Lactate dehydrogenase A; MCT: Monocarboxylate transporter; N/A: Not applicable.

Targeted degradation and novel approaches

Engineered bacterial lactyl-CoA hydrolase fused to a nuclear localisation signal selectively depleted nuclear lactyl-CoA, attenuated tumour growth without systemic toxicity in orthotopic PDAC models[29]. Targeting lactylation erasers also presents a unique opportunity. For instance, activating SIRT2 could potentially suppress oncogenic lactylation programs. The therapeutic feasibility of targeting erasers vs writers depends on the specific context, the desired outcome (inhibiting a writer vs activating an eraser), and the development of isoform-specific modulators with good drug-like properties.

CONCLUSION

Lactylation integrates oncogenic metabolism with epigenetic and DNA-repair circuitry in PDAC. Targeting this modification or its upstream metabolic enzymes provides a rational strategy to reverse lineage plasticity, overcome chemoresistance, and bolster immunotherapy. However, the field must move beyond correlative evidence to establish direct causality, which requires the development of more precise molecular tools that can specifically manipulate lactylation without affecting parallel modification pathways. Future work must refine isoform-specific writers/erasers, delineate lactylation crosstalk with other acylations, and validate predictive biomarkers to bring lactylation-targeted therapy to the bedside. A critical and balanced view of both the promise and the pitfalls of this emerging field will be essential for its successful translation.

ACKNOWLEDGEMENTS

The authors thank their colleagues in the Department of Hepatobiliary Surgery at the First Affiliated Hospital of Wannan Medical College for their insightful discussions and constructive feedback during the conceptualization of this review. We also extend our appreciation to the clinical research coordinators for their supportive role.