Targeting epigenetic networks to overcome cisplatin resistance in ovarian cancer: from mechanisms to clinical translation.

Ovarian cancer patients with platinum resistance face a dismal five-year survival rate of only 30%, owing to the limited efficacy of current therapeutic options. Existing research often focuses on individual epigenetic modifications, which hampers a systematic understanding of resistance mechanisms and their clinical translation. To address this, our review integrates current evidence to propose an “Epigenetic Resistance Stability Network” model, which comprises three core components: (i) four foundational layers, each with distinct roles in cisplatin resistance. These include DNA methylation (e.g., SFRP5 hypermethylation activating the Wnt pathway), non-coding RNAs (ncRNAs), RNA modifications, and histone modifications, which govern gene expression, post-transcriptional regulation, RNA function, and chromatin architecture, respectively. (ii) three interactive networks: “DNA methylation/miRNA feedback loops,” “lncRNA/histone modification cascades,” and “circRNA/m6A synergistic stabilization.” These networks sustain the resistant phenotype by interlinking key nodes across the four foundational layers. (iii) a theoretical framework encompassing two parts: the “Epigenetic Compensation Network” theory (explaining how tumors evade single-target therapies) and the “Epigenetic Temporal Regulation” model (outlining resistance progression: “miRNA response → methylation consolidation → chromatin stabilization”). Building on this model, we outline a translational roadmap involving “biomarker validation (e.g., SFRP5 methylation, circITGB6),” “combination therapy development,” and “personalized intervention,” offering novel insights for overcoming cisplatin resistance and improving patient outcomes in ovarian cancer.