Epigenetic and mitoepigenetic regulation in cancer and therapeutic perspectives

Epigenetic modifications on nuclear and mitochondrial DNA constitute key regulatory layers influencing the transcriptional, metabolic, and phenotypic adaptability of cancer cells. The canonical principles of epigenetic control encompass DNA methylation, histone modification, and non-coding RNA–mediated regulation, which collectively contribute to the silencing of tumor suppressor genes, the activation of oncogenes, and chromatin remodeling. Therefore, epigenetic drugs (epi-drugs) are of great interest in the development of new-generation therapeutics and holistic treatment approaches. Accordingly, this work presents a narrative review that integrates current evidence on the molecular mechanisms, therapeutic developments, and translational relevance of epigenetic and mitoepigenetic regulation in cancer. RNA–mediated regulation collectively contributes to the silencing of tumor suppressor genes and to the activation of oncogenes. The field of mitoepigenetics encompasses mitochondrial DNA (mtDNA) methylation, RNA modifications, and post-translational regulation of mitochondrial proteins such as TFAM, DNMT1, and sirtuins, which influence oxidative phosphorylation, redox balance, and apoptotic pathways, thereby affecting tumor initiation, progression, and treatment response. Recent advances in epigenetic drug development include FDA-approved DNMT and HDAC inhibitors and newer agents targeting EZH2, IDH1/2, and DOT1L, which broaden the scope of precision oncology. In addition, modulation of mitochondrial epigenetic mechanisms has been identified as a potential approach for addressing metabolic reprogramming and therapeutic resistance in cancer. The convergence of nuclear and mitochondrial regulatory frameworks reveals the critical need for biomarker-informed, combinatory, and organelle-targeted therapeutic approaches to sustain treatment efficacy. Comprehensive characterization and pharmacological targeting of epigenetic and mitoepigenetic networks provide a structured basis for developing personalized and metabolism-informed interventions in cancer therapy.