circMAN1A2 as an Isoform-Resolved Circular RNA Hub in Cancer

Circular RNAs (circRNAs) are covalently closed transcripts generated by spliceosome-mediated back-splicing. Their high stability and tissue-, cell-state-, and disease-context specificity support roles as cancer regulators and biomarkers. circMAN1A2, derived from the MAN1A2 locus, is recurrently dysregulated across malignancies. This review aims to summarize current knowledge of circMAN1A2 biology and evaluates its mechanistic and translational relevance in cancer. Emerging evidence indicates that circMAN1A2 should be considered an isoform-resolved RNA hub. Alternative circularization generates multiple isoforms, whereas cancer tissues often show dominance of a predominantly expressed isoform. Functionally, circMAN1A2 extends beyond microRNA sponging to protein binding, proteostasis regulation, and direct circRNA-mRNA pairing mediated by the back-splice junction. Its biological effects are highly context dependent: circMAN1A2 promotes oncogenic phenotypes in several epithelial cancers, but can suppress glioblastoma by inducing ferroptosis and remodeling the immune microenvironment. We integrate evidence on circMAN1A2 isoforms, biogenesis, interactome modules, and cancer-type-specific phenotypes; highlight experimental and quantitative limitations, particularly in competing endogenous RNA models; and propose a translational route for biomarker development and therapeutic targeting, including back-splice-junction-directed oligonucleotides and isoform restoration. Reproducible, isoform-specific standards will be essential for defining the clinical actionability of circMAN1A2.