Paschalis Barboutis

Erectile dysfunction (ED) is a prevalent condition involving multiple molecular mechanisms. Although non-coding RNAs have emerged as important regulators of gene expression, the role of circular RNAs (circRNAs) in ED remains poorly defined. CircRNAs are characterised by a covalently closed loop structure that confers enhanced stability and enables diverse regulatory functions. This review aims to investigate the potential interactions between circRNAs and the signalling pathways linked to ED. Only two primary studies directly investigating circRNA dysregulation in ED were identified, highlighting the early stage of this field. This hybrid systematic narrative review combines a PRISMA-guided systematic search with a pre-specified, hypothesis-generating narrative synthesis of the broader circRNA literature across key signalling pathways implicated in ED, including the NO/cGMP/PKG, RhoA/ROCK, JNK/c-Jun/Bak, and TNF-α/NF-κB axes. We identify several circRNAs as potential regulators of endothelial dysfunction, inflammation, and smooth muscle contractility. CircRNAs therefore emerge as candidate biomarkers and potential therapeutic targets. Given that direct evidence is currently limited to two animal studies, with no circRNA validated in human tissue or as a biomarker, these molecules should be regarded only as candidates for future biomarker and therapeutic target validation.