Extrachromosomal circular DNA drives dynamic genome plasticity: emerging roles in disease progression and clinical potential.

Extrachromosomal circular DNA (eccDNA) has emerged as a dynamic and versatile genomic element with key roles in physiological regulation and disease pathology. This review synthesizes current knowledge on eccDNA, covering its classification, biogenesis, detection methods, biological functions, and clinical implications. Once considered rare anomalies, eccDNAs are now recognized as major drivers of oncogene amplification, genomic plasticity, and therapeutic resistance, particularly in cancer. EccDNA subtypes such as microDNA, double minutes, and ecDNA are defined by their structural, genomic, and pathological features. EccDNAs originate through diverse mechanisms including DNA repair, chromothripsis, breakage fusion bridge cycles, and apoptosis, occurring in both normal and stressed cells. Advances in long-read and single-cell sequencing, CRISPR-based synthesis, and computational tools have improved detection and functional analysis. Functionally, eccDNAs contribute to transcriptional amplification, activate immune responses through cGAS-STING signaling, and facilitate intercellular communication. They are found across a range of tissues and disease states-including cancer, cardiovascular, neurological, autoimmune, and metabolic disorders-and serve as both biomarkers and regulatory elements. We introduce the concept of the stress selection theory, which proposes eccDNA as an adaptive reservoir that enhances cellular fitness in response to environmental and therapeutic pressures. Despite growing insights, challenges remain in understanding tissue-specific roles, achieving clinical translation, and standardizing methodologies. Emerging tools in multi-omics, spatial biology, and artificial intelligence are expected to drive future breakthroughs in precision medicine.