Tabriz University of Medical Sciences Advanced Pharmaceutical Bulletin 2228-5881 16 2 2026 06 15 Epigenetic Regulation of Cell Cycle Control in Colorectal Cancer: Molecular Mechanisms and Therapeutic Perspectives 307 317 10.34172/apb.47190 EN Srinivasa B https://orcid.org/0000-0002-7512-0555 Devika P Jeeragyal https://orcid.org/0000-0001-8514-0675 Kiran Velukuri https://orcid.org/0009-0003-6371-4895 Amarnath Reganti https://orcid.org/0009-0000-8835-7976 Vaheedha S https://orcid.org/0009-0003-9557-9499 Vinodhkumar Ramalingam https://orcid.org/0000-0002-5269-0520 Rajasekar Sreerama https://orcid.org/0000-0002-2287-2286 Neelima Grandhe https://orcid.org/0000-0003-0298-8705 Praveen Hoogar https://orcid.org/0000-0003-2170-5643 REVIEW 10.34172/apb.47190 2026 02 14 2026 05 07 Introduction: Epigenetic dysregulation is increasingly recognized as a fundamental driver of cell cycle checkpoint failure in colorectal cancer. Beyond genetic mutations, epigenetic mechanisms provide a dynamic and potentially reversible layer of control over cyclin-dependent kinase activity and tumor progression. This mechanistic critical review examines how epigenetic alterations reshape cell cycle regulation in colorectal cancer and evaluates their translational relevance. Methods: This review adopts a critical mechanistic approach, integrating and interpreting evidence from experimental, translational and clinical studies addressing epigenetic regulation of cell cycle control in colorectal cancer. Rather than following a systematic review framework, the literature was evaluated conceptually to identify dominant mechanisms, areas of convergence and unresolved controversies. Results: Evidence indicates that aberrant DNA methylation, histone modifications and chromatin remodeling converge to repress key cyclin-dependent kinase inhibitors including p16INK4a, p21Cip1 and p27Kip1. These epigenetic alterations sustain cyclin–CDK activity thereby promote bypass of G1/S checkpoint control and facilitate uncontrolled proliferation. Importantly, epigenetic heterogeneity across colorectal tumors contributes to variable therapeutic responses and resistance to both conventional and epigenetic-targeted therapies. Conclusion: Epigenetic control of cell cycle checkpoints represents a central and therapeutically exploitable mechanism in colorectal cancer. A mechanistic understanding of these regulatory networks highlights opportunities for rational combination strategies and precision-based interventions while underscoring current knowledge gaps that warrant further investigation.