Editorial: Circular RNAs: from anomalies to cellular regulators

The Research Topic 'Circular RNAs: From Anomalies to Cellular Regulators' curates a multidisciplinary collection of insights that push the conceptual boundaries of the field. By moving beyond the traditional ceRNA paradigm, these contributions illuminate the role of circRNAs as dynamic architects of gene expression, acting across successive layers of molecular complexity-from broad transcriptomic networks to the precise calibration of specific signalling axes.In this context, the study by Chang et al. provides compelling evidence of how circRNAs can modulate pathogenic mechanisms, reinforcing the view of circRNAs as upstream modulators of complex diseaserelated pathways. Focusing on intrauterine adhesion (IUA), a condition characterized by endometrial fibrosis, the authors combined transcriptomic profiling with integrative bioinformatic analyses to identify differentially expressed circRNAs and to provide circRNA-miRNA-mRNA regulatory networks (ceRNETs) associated with extracellular matrix remodelling. Within these, hsa_circ_0000994 and hsa_circ_0000439 emerged as key regulatory actors, as supported by the silencing of hsa_circ_0000994 that resulted in a marked reduction of fibrosis-related markers. In line with these results, pathway enrichment analyses performed by Chang and co-authors revealed the activation of major signalling cascades including NF-κB and Notch, both critically implicated in inflammation and fibrosis, thereby linking circRNA dysregulation to well-established pathogenic pathway.Shi et al. further refine this regulatory concept by describing a circRNA-mediated axis in eosinophilic chronic rhinosinusitis (ECRS), a highly treatment-resistant inflammatory condition. By comparing nasal polyp tissues from ECRS patients with non-inflammatory controls, the authors identified a distinct expression pattern characterized by upregulation of circRNA_0021727 and its downstream target ADAM12, alongside downregulation of miRNA_145_5p. These findings support the existence of a circRNA_0021727-miRNA_145_5p-ADAM12 regulatory axis, in which the circRNA acts upstream by modulating miRNA In obesity-linked cancers, circRNAs participate in the intersection between metabolic reprogramming, inflammation and tumor progression. CircSAMD4A links adipocyte differentiation and lipid accumulation to systemic metabolic alterations, while circACC1 and circ-MAT2B drive tumor metabolic flexibility by regulating AMPK signalling and HIF-1α-mediated glycolysis, respectively. In parallel, inflammation-driven circMRCKa induced by tumor-associated macrophages further connect immune signalling to cancer cell metabolic adaptation. Overall, these findings illustrate circRNAs as mediators of intercellular communication within the obesity-altered microenvironment. Despite strong correlative evidence, functional validation in integrated models and longitudinal studies remains limited. Nevertheless, circRNAs such as circHIPK3, CDR1as, circACC1, circANRIL, and circ-Foxo3 consistently emerge as central nodes across these interconnected disease networks.Collectively, the contributions within this Research Topic provide compelling evidence for a paradigm shift, firmly establishing circRNAs as sophisticated molecular protagonists rather than mere transcriptional relics.Across a diverse pathological landscape, these molecules have emerged as pivotal integrators of metabolic, inflammatory and tumor signalling. Consequently, circRNAs transcend their utility as diagnostic biomarkers; they represent a frontier of upstream therapeutic intervention, necessitating a deeper integration into the frameworks of fundamental cell biology and the burgeoning field of precision medicine.