CircERBB2 and beyond: a new regulatory layer in HER2-driven cancer

Abstract Human epidermal growth factor receptor 2 ( HER2 , also known as ERBB2 ) is aberrantly expressed in multiple malignancies and serves as both a key molecular tumor classification marker and an important therapeutic target. Although monoclonal antibodies, tyrosine kinase inhibitors, and antibody–drug conjugates targeting HER2 have significantly improved patient outcomes, challenges such as treatment resistance and disease relapse remain. To address these unmet clinical needs, circular RNAs (circRNAs) have emerged as key regulators of tumorigenesis, therapeutic resistance, and immune modulation because of their structural stability, tissue specificity, and multifaceted regulatory capabilities. Accumulating evidence indicates that circRNAs derived from the HER2 gene, particularly circular RNA ERBB2 (circERBB2), participate in cancer progression through multiple mechanisms, including microRNA sponging, functional peptide translation (e.g., HER2-103), and rDNA transcriptional regulation. Moreover, circRNAs have been shown to modulate HER2 heterodimerization and downstream signaling activation, thereby promoting tumorigenesis and drug resistance. Beyond their mechanistic roles, circRNAs hold translational potential as diagnostic biomarkers, prognostic indicators, and therapeutic targets, with applications ranging from liquid biopsy-based assays to circRNA-targeted therapies and vaccines. This review summarizes the current advances in circRNA-mediated regulation of HER2 and its heterodimers, focusing on circERBB2, and highlights emerging insights that may help overcome treatment resistance and improve HER2-targeted therapeutic strategies.