The HDAC–Lactylation Axis in Cancer Chemoresistance: A Metabolic–Epigenetic Interface

Chemoresistance remains a critical obstacle in cancer therapy, shaped not only by genetic mutations but also by reversible metabolic and epigenetic adaptations. Enhanced glycolysis and lactate accumulation are associated with tumor fitness before and during therapy and position lactate as more than a metabolic byproduct, enabling it to act as a regulatory metabolite through lysine lactylation of histone and non-histone proteins. This review examines the HDAC–lactylation axis as a metabolic–epigenetic interface and asks whether HDAC-mediated regulation of lactylation causally influences chemotherapy resistance or sensitization. We summarize evidence on lactate production, protein lactylation in cancer, and class I histone deacetylases (HDAC1–3) as delactylases, highlighting the reversible nature of this modification. Current evidence implicates histone and non-histone lactylation in two processes relevant to chemotherapy response: histone lactylation-dependent transcriptional programs involved in metabolic stress responses and phenotypic plasticity, and direct regulation of non-histone proteins involved in DNA repair, RNA processing, genome stability, and cellular stress adaptation. Together, these findings suggest that the HDAC–lactylation axis functions as a dynamic metabolic–epigenetic regulatory network enabling context-dependent adaptive responses. HDAC isoform-focused pharmacological and genetic perturbation, inhibition of lactate dehydrogenase A (LDHA) or monocarboxylate transporter 1 (MCT1), suppression of monocarboxylate transporter 4 (MCT4), and site-specific lactylation proteomics using liquid chromatography–tandem mass spectrometry (LC-MS/MS) could clarify the contribution of this axis to chemotherapy response.