Lactylation in pancreatic cancer: From molecular mechanisms to therapeutic perspectives

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.