Epigenomic Remodeling by Lipid Metabolism: A Cross-Disease Perspective on Cancer and Brain Disorders

Lipid metabolism is no longer viewed simply as a source of membrane biomass or ATP. It is now proposed as a regulatory system that determines which metabolites reach the nucleus, which chromatin-modifying enzymes are engaged, and which transcriptional states become stable during disease progression. This review develops a mechanistic cross-disease framework emphasizing metabolite flux, subcellular compartmentalization, cell-type specificity, and the temporal persistence of chromatin states. We synthesize recent evidence linking lipid metabolism to chromatin remodeling in cancer, Alzheimer’s disease, and Parkinson’s disease, and we highlight how emerging single-cell multi-omics and spatial lipidomics may shape potential metabolism-targeted epigenetic therapies. In both cancer and brain disorders, lipid flux alters the availability of acetyl-CoA, S-adenosylmethionine, NAD+, and bioactive fatty acid derivatives, thereby reshaping histone acetylation, DNA and histone methylation, chromatin accessibility, and transcription-factor activity. In cancer, de novo lipogenesis, acetate scavenging, fatty acid oxidation, and phospholipid remodeling sustain nuclear acetyl-CoA pools, promote oncogenic super-enhancers, and support survival under hypoxia, acidosis, and therapy stress. In neurodegenerative disease, mitochondrial dysfunction, cholesterol dyshomeostasis, sphingolipid imbalance, oxysterol accumulation, and microglial lipid droplet formation may distort the epigenetic programs required for neuronal maintenance, synaptic plasticity, and inflammatory resolution. However, neurodegenerative disorders are not uniformly hypoacetylated; instead, they exhibit stage-, region- and cell-type-specific chromatin remodeling, with hypoacetylation at some vulnerable loci coexisting with hyperacetylation at others. By comparing lipid–epigenome coupling across proliferative and degenerative conditions, we argue that the same metabolic nodes can yield markedly different pathological outcomes depending on cellular context, providing a basis for more precise therapeutic design.