Natural compounds as epigenetic modulators in gynaecological cancers: From chemoresistance to precision oncology

Gynaecological cancers, including ovarian, cervical, and endometrial malignancies, remain major causes of cancer-related morbidity and mortality because of tumour heterogeneity, recurrence, and therapeutic resistance. Epigenetic dysregulation, involving aberrant DNA methylation, altered histone modifications, dysregulated non-coding RNAs, and N⁶-methyladenosine (m⁶A) RNA remodelling, contributes to these processes. Direct evidence that natural compounds modulate m⁶A machinery in gynaecological cancers remains absent and is considered a knowledge gap.

We synthesised evidence on epigenetic alterations in gynaecological cancers and critically evaluated dietary and plant-derived compounds as candidate epigenetic modulators, focusing on preclinical mechanistic studies, pharmacokinetic data, selected early-phase clinical studies, and computational approaches to compound discovery and biomarker stratification.

Natural agents, including curcumin, epigallocatechin-3-gallate, sulforaphane, berberine, resveratrol, genistein, diindolylmethane, quercetin, capsaicin, and butyrate, have been reported, mainly in preclinical models, to modulate DNA methyltransferases, histone deacetylases, microRNA networks, tumour suppressor gene expression, and chemosensitivity. However, translation is limited by poor bioavailability, pharmacokinetic variability, insufficient tumour-tissue target-engagement data, weak potency compared with approved epigenetic drugs, limited patient-derived model validation, and a lack of biomarker-driven trials. Compound-specific evidence remains uneven, with stronger support for selected chemosensitising mechanisms than for direct clinical epigenetic efficacy.

Natural compounds are mechanistically plausible but clinically under-validated adjunctive epigenetic modulators. Future development requires standardised formulations, improved delivery systems, tumour-tissue pharmacodynamic validation, multi-omics profiling, patient stratification, and biomarker-guided clinical trials to define their realistic role in precision gynaecological oncology. The proposed translational framework may support rational prioritisation of candidates for future preclinical and clinical testing.