Lipid metabolism and chromatin-associated sirtuin-dependent epigenetic reprogramming in cancer

Lipids are essential components of cancer biology, serving not only as sources of energy and biomass but also as signalling molecules that influence gene regulation and cellular plasticity. Increasing evidence suggests that lipid metabolic rewiring can shape epigenetic states through the activity of sirtuins, a family of NAD+-dependent enzymes with deacetylase, deacylase and ADP-ribosyltransferase activities that couple metabolic cues to chromatin regulation. This narrative review examines how alterations in fatty acid oxidation, lipid uptake, cholesterol metabolism and lipid-derived metabolites converge on the sirtuin family of NAD+-dependent enzymes to regulate epigenetic states in cancer. Lipid metabolism shapes sirtuin function by influencing NAD+/NADH balance, acetyl-CoA availability and the production of diverse acyl-CoA species, thereby modulating histone acetylation, non-canonical lysine acylations and DNA methylation programmes. In parallel, lipid metabolites can directly regulate sirtuin abundance, activity and subcellular localization, with context-dependent consequences for chromatin regulation and transcriptional plasticity. Emerging evidence indicates that this lipid-sirtuin-epigenetic axis contributes to metabolic adaptation and tumour cell fitness, stemness, antitumour immunity and metastatic dissemination. The dual nature of sirtuin signalling is also discussed, as these enzymes can either promote or constrain tumour progression depending on the metabolic and microenvironmental context. Therapeutic opportunities targeting lipid metabolism and sirtuins are considered, together with the potential of lipid, sirtuin and epigenetic signatures as biomarkers for prognosis, patient stratification and precision oncology.