Cross-Regulation Between DNA Methylation and Circadian Clock Reprogramming in Ovarian Cancer: Mechanistic Insights, Biomarker Potential, and Therapeutic Implications.

Early diagnosis remains challenging, recurrence rates remain high, and platinum resistance frequently develops in ovarian cancer (OC), collectively representing major barriers to long-term patient survival. DNA methylation (DNAm), as a relatively stable yet dynamically modifiable epigenetic signature, can capture alterations in tumor states and evolutionary trajectories associated with therapeutic pressure. Meanwhile, the circadian rhythm system regulates multiple cancer-related processes, including DNA damage repair, cell-cycle progression, metabolic adaptation, and immune microenvironment remodeling, thereby influencing OC development and treatment responses. Accumulating evidence suggests the existence of a bidirectional interplay between DNAm landscapes and the circadian clock network in OC. This review summarizes the emerging mechanisms underlying the crosstalk between DNAm and circadian reprogramming in OC, and further discusses their potential applications in early detection, prognostic stratification, dynamic monitoring of platinum resistance, and chronotherapy-based therapeutic strategies. Although current findings highlight the promising translational potential of the DNAm-circadian axis, its clinical implementation remains constrained by tumor heterogeneity, variations in sampling time points, cellular composition complexity, and insufficient validation across experimental models and clinical cohorts. Future integration of time-resolved sampling approaches, liquid biopsy platforms, single-cell and spatial epigenomic technologies, as well as prospective clinical trials evaluating circadian-guided interventions, may further define the translational boundaries and clinical utility of DNAm-circadian coupling in precision diagnosis and treatment of OC.