Circular RNAs (circRNAs) have emerged as stable post-transcriptional regulators that influence gene expression, cellular adaptation, and disease pathogenesis through mechanisms including microRNA (miRNA) interaction, RNA-binding protein modulation, and signaling-network regulation. Generated through the back-splicing process that produce covalently closed RNA loops, circRNAs exhibit remarkable stability, evolutionary conservation, and tissue-specific expression patterns, enabling them to function as miRNA sponges, protein scaffolds, transcriptional modulators, and, in some cases, translational templates. Increasing evidence indicates that dysregulated circRNA expression contributes to a broad spectrum of human diseases, highlighting their diagnostic and therapeutic potential. Among the molecular pathways influenced by circRNAs, Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase and a modulator of metabolic homeostasis, stress adaptation, inflammation, autophagy, and aging, has emerged as a particularly important target. Recent studies have revealed that circRNAs regulate SIRT1 through complex post-transcriptional and signaling networks, thereby influencing cellular fate decisions in both malignant and non-malignant disorders. Importantly, the biological consequences of circRNA-mediated SIRT1 modulation appear highly context-dependent, with protective or pathogenic effects varying according to tissue type, metabolic state, and disease stage. In this review, we provide a comprehensive and integrative discussion of the circRNA-SIRT1 regulatory axes across diverse pathological conditions, from common metabolic disorders to life-threatening cancers. Beyond summarizing current evidence, we propose the circRNA-SIRT1 network as a context-dependent post-transcriptional regulatory network linking non-coding RNA (ncRNA) biology to immunometabolic and stress-response pathways. We further discuss emerging translational opportunities and circRNA-targeted therapeutics, emphasizing the potential of this regulatory axis as a promising platform for precision diagnostics and disease-specific therapeutic interventions.
