Circular RNAs at the crossroads of oxidative stress: novel targets for precision therapeutics

Abstract

Oxidative stress is a major pathogenic driver across disorders in which persistent redox imbalance promotes cellular injury, inflammation, mitochondrial dysfunction, and maladaptive survival responses. Circular RNAs (circRNAs) have emerged as post-transcriptional regulators of these processes by modulating circRNA–miRNA–mRNA networks, antioxidant gene programs, redox-sensitive signalling pathways, and ROS-generating enzymes. This review examines how circRNAs influence Nrf2, NF-κB, MAPK, PI3K/AKT, mitochondrial, and cell-death pathways in cancer, neurodegenerative, cardiovascular, and metabolic diseases. Rather than cataloguing disease-associated circRNAs, we apply a redox-centred, evidence-tiered, and context-dependent framework that distinguishes mechanistic support from associative findings and highlights why the same circRNA may exert protective or pathogenic effects across tissues and disease states. We further evaluate the diagnostic potential of circulating and tissue-specific circRNAs and the therapeutic relevance of synthetic circRNAs, antisense strategies, and CRISPR/Cas-based modulation. These approaches may enable pathway-directed biomarker development and targeted redox intervention, but their clinical value remains constrained by limited human validation, inconsistent circRNA and ROS assays, off-target effects, delivery barriers, immunogenicity, and uncertainty regarding host-gene disruption. Standardized methodologies, longitudinal cohorts, and integrated multi-omics studies are therefore required to establish causality, reproducibility, and translational readiness.

Graphical abstract

Keywords

CircRNA–miRNA–mRNA axis / Oxidative stress / Reactive oxygen species / Nrf2 signalling pathway / Redox homeostasis / Antioxidant defense mechanisms / CRISPR/Cas circRNA biomarkers

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