Beyond linear: How circRNAs twist and turn Notch signaling

Circular RNAs (circRNAs) have emerged as pivotal regulators of the Notch signaling pathway, influencing diverse pathological processes ranging from cancer to neurodegenerative disorders. This review synthesizes evidence demonstrating how circRNAs modulate Notch activity through miRNA sponging (e.g., circ-NOTCH 1 promoting gastric cancer metastasis via miR-637/apelin axis), protein interactions, and peptide encoding. Key examples of oncogenic circRNAs are circNFIX (glioma) and circ-ASH2L (pancreatic cancer), which drive tumor progression by sponging miR-34a-5p, elevating NOTCH 1 expression, and activating downstream effectors. We also discuss tissue-specific duality of circRNAs. In fact, Notch signaling exhibits context-dependent roles, with circFBXW7 suppressing NOTCH 1 in T-ALL (tumor suppressor) versus circ-NSD2 activating JAG1/NOTCH 1 in colorectal cancer (oncogene). While circRNAs like hsa_circ_0001741 show prognostic promise, challenges persist in delivery and target specificity due to miRNA pleiotropy. By integrating mechanistic insights with preclinical examples, this review highlights circRNAs as both biomarkers and therapeutic targets, urging further research to address clinical translation barriers.