Lactylation in pancreatic cancer: From molecular mechanisms to therapeutic perspectives

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.

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.