Recent advances in coronary in-stent restenosis: a comprehensive narrative review.

Coronary in-stent restenosis (ISR) remains an important limitation of percutaneous coronary intervention despite the use of drug-eluting stents. ISR is a heterogeneous process driven by neointimal hyperplasia, neoatherosclerosis, and mechanical factors such as stent underexpansion or fracture. Intravascular imaging, particularly IVUS and OCT, enables mechanism-guided lesion preparation and device selection, while metabolomics, molecular imaging, and circulating biomarkers are improving understanding of its biological heterogeneity. Adequate lesion preparation is fundamental, and drug-coated balloons and repeat drug-eluting stent implantation remain the principal treatment strategies. Adjunctive techniques such as intravascular lithotripsy may help in severely calcified or resistant underexpanded lesions. Emerging evidence also implicates sphingolipid metabolism, mitochondrial dysfunction, immune-inflammatory signaling, and systemic metabolic modulation in ISR, though clinical relevance requires validation. This review summarizes recent advances in the epidemiology, pathophysiology, risk factors, diagnosis, treatment, and prevention of ISR, emphasizing the shift from anatomy-based management toward mechanism-guided, individualized therapy.