Circular RNAs: Epigenetic Puppeteers Pulling the Strings of Cancer Pathogenesis

ABSTRACT Circular RNAs (circRNAs), a unique class of endogenous noncoding RNAs characterized by their covalently closed loop structure, have emerged as pivotal players in cancer biology due to their exceptional stability, tissue‐specific expression, and diverse regulatory functions. This comprehensive review delves into the multifaceted roles of circRNAs as epigenetic modulators in cancer pathogenesis, systematically exploring their biogenesis via back‐splicing—regulated by cis ‐elements and trans ‐factors—and their general functions, including directly recruiting chromatin‐modifying enzymes or DNA methyltransferases or by sequestering noncoding RNAs that feed back to the chromatin, thereby establishing heritable and DNA sequence–invariant expression states. A distinctive feature of this work is its focused examination of how circRNAs interface with key epigenetic regulators, such as histone modifiers, DNA methyltransferases, and chromatin remodeling complexes, thereby influencing gene expression and driving tumor initiation, metastasis, and drug resistance. The review further integrates recent insights from single‐cell sequencing and discusses stoichiometric and structural nuances that define authentic miRNA sponge functions, setting it apart from previous summaries. By synthesizing current evidence and highlighting both mechanistic depth and clinical relevance—such as the potential of circRNAs as biomarkers and therapeutic targets—this article not only advances our understanding of circRNA‐mediated epigenetic dysregulation in cancer but also outlines future research directions and technological challenges, underscoring its significance in bridging basic molecular insights with translational oncology.