Engineered Multifunctional Hydrogel Delivering Novel CBX7 Inhibitor Modulates Cuproptosis Via Liquid-Liquid Phase Separation to Restore Cardiac Function in Aged Myocardial Infarction.

Jun Liu, Peng Qu, Jiao Shi, Tingting Liang, Yao Gu, Xue Li, Cui Ma, Danyang Zhao, Feila Liu, Qi Liang, Panke Cheng, Qian Lei

Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China. · pubmed

Paper

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, O

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Research summary

The study claims that inhibiting CBX7 can restore cardiac function in aged hearts by modulating cuproptosis through liquid-liquid phase separation. This research addresses a mechanism related to aging and cardiac repair, which is crucial for understanding and potentially mitigating age-related decline in heart function.

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