Abstract:Cardiac repair after myocardial ischemia–reperfusion (MIR) declines with aging. This study shows that Chromobox 7 (CBX7) acts in an age‐dependent manner, in young hearts, it promotes cardiomyocyte proliferation, whereas in aged hearts, CBX7 forms liquid–liquid phase separation (LLPS) with ATP7A, trapping ATP7A intracellularly, reducing membrane trafficking and copper efflux, and triggering cuproptosis. High‐throughput screening identifies δ‐Amyrenone (δAe) as a selective CBX7 inhibitor that disrupts CBX7‐ATP7A LLPS, restores ATP7A trafficking and copper efflux, and improves cardiac function while reducing fibrosis and arrhythmias. Single‐cell RNA‐seq shows MIR‐induced cuproptosis‐related loss is concentrated in NR4A3 positive cardiomyocytes and RGCC positive capillary endothelial cells in aged hearts. To enhance delivery, this study engineered a multifunctional conductive hydrogel with antioxidant, pro‐angiogenic, immunomodulatory, O2 releasing and electrical properties. Loaded with δAe, this single‐injection hydrogel provides controlled release, alleviates cuproptosis‐related mitochondrial injury, and pairs its intrinsic repair capacity with CBX7 inhibition to drive ATP7A trafficking, enhance copper efflux, and suppress cuproptosis. In aged mouse and Bama minipig MIR models, this strategy improves structural, functional, and electrophysiological outcomes, supporting translational potential.
