EZH2 in Ovarian Cancer: Mechanistic Dependencies, Therapeutic Platforms and Translational Combinations

Ovarian cancer remains the deadliest gynecologic malignancy because most patients present with advanced disease and ultimately relapse despite surgery, platinum- based chemotherapy, and modern maintenance strategies. Enhancer of zeste homolog 2 (EZH2), the catalytic core of polycomb repressive complex 2, has emerged as a context-dependent epigenetic regulator that links chromatin repression to cellular plasticity, repair-state adaptation, stemness, metabolism, and immune remodeling. This review aims to define the clinical relevance of context-dependent EZH2 states in ovarian cancer and compare the therapeutic logic, evidence maturity, and limitations of available EZH2-targeting platforms.

We conducted a focused narrative synthesis of ovarian-cancer-relevant preclinical studies, medicinal-chemistry reports, and clinical evidence, supplemented by targeted PubMed searches and ClinicalTrials.gov checks during revision. Evidence was interpreted in light of biologic context, therapeutic platform, combination rationale, and the degree of ovarian-specific clinical support.

Current evidence supports a role for EZH2 in ovarian tumor progression through canonical polycomb repressive complex 2-dependent mechanisms and, in selected contexts, non-canonical functions. Therapeutic development now includes catalytic inhibitors, dual EZH1/2 inhibitors, EEDdirected inhibitors, degraders, and RNA-based strategies. In ovarian cancer, the strongest mechanistic rationale currently supports combinations with platinum chemotherapy and poly(ADP-ribose) polymerase inhibition, whereas immune-oriented and broader cotargeting strategies remain promising but less mature.

The key translational question is not simply whether EZH2 can be pharmacologically engaged, but which form of EZH2 dependency is present, in which biologic context, and with which partner therapy. Catalytic inhibition alone may underperform when adaptive redundancy, polycomb complex architecture, or non-canonical protein function sustain tumor fitness.

EZH2 should be viewed not as a uniformly validated ovarian-cancer target, but as a context-dependent vulnerability whose most defensible near-term clinical positioning is biomarkerinformed combination development rather than unselected monotherapy.