Cross-regulation of trophoblast function by DNA methylation, histone modification, and metabolism: Epigenetic–metabolic crosstalk in placental disorders and offspring metabolic programming

Background Trophoblast cells are core components of the placental tissue. Abnormalities in their differentiation, invasion, and material exchange functions directly lead to placenta-originated pregnancy disorders, including preeclampsia (PE), gestational diabetes mellitus (GDM), and fetal growth restriction (FGR). Key metabolites from glucose-lipid metabolism act as co-substrates or cofactors for epigenetic modifiers, linking maternal metabolic disturbances to trophoblast dysfunction and offspring metabolic programming. Objectives This review aims to systematically summarize the molecular mechanisms and research progress regarding the cross-regulation of trophoblast cell function by DNA methylation, histone modification, and glucose-lipid metabolism, with a focus on the molecular pathways and key nodes of this cross-regulation, thereby providing a theoretical reference for the early prediction and intervention of placenta-originated pregnancy disorders. Methods This review synthesizes findings from multi-omics integration, single-cell and spatial multi-omics, and trophoblast organoid studies, alongside evidence from human cohorts, animal models, and epigenome editing systems. Results The placental genome is characterized by global hypomethylation. The statuses of histone acetylation, methylation, and novel acylation modifications are all modulated by metabolites. DNA methylation and histone modifications act synergistically through physical interactions and core metabolic nodes to collectively determine trophoblast differentiation and function. High glucose exposure induces persistent epigenetic alterations, whereas lipotoxicity inhibits key epigenetic enzymes; both factors drive trophoblast dysfunction. In PE, a metabolism–epigenetic feedback loop exists, further exacerbating placental injury. A central mechanistic cascade emerges: maternal metabolic disturbances reshape the availability of key metabolites (e.g., SAM, acetyl-CoA, α-KG); these metabolites directly modulate the activities of DNA methyltransferases, TET dioxygenases, histone acetyltransferases, and demethylases; the resultant epigenetic rewiring programs trophoblast differentiation, invasion, and syncytialization. Conclusion Trophoblast dysfunction ultimately drives placental disorders and programs offspring metabolic health across generations. Future clinical translation should focus on precision nutritional interventions and the development of combined metabolic–epigenetic biomarkers.