Engineered Multifunctional Hydrogel Delivering Novel CBX7 Inhibitor Modulates Cuproptosis Via Liquid-Liquid Phase...

Area of Science:

• Cardiovascular Biology
• Aging Research
• Mitochondrial Medicine

Background:

• Cardiac repair after myocardial ischemia-reperfusion (MIR) diminishes with age.
• Chromobox 7 (CBX7) plays an age-dependent role in cardiac function.

Purpose of the Study:

• To investigate the age-dependent mechanism of cardiac repair after MIR involving CBX7.
• To identify therapeutic strategies to counteract age-related cardiac dysfunction.

Main Methods:

• High-throughput screening identified δ-Amyrenone (δAe) as a CBX7 inhibitor.
• Single-cell RNA-sequencing analyzed MIR-induced cellular changes in aged hearts.
• A multifunctional hydrogel was engineered for targeted drug delivery.

Main Results:

• In aged hearts, CBX7 forms liquid-liquid phase separation (LLPS) with ATP7A, leading to intracellular copper trapping, reduced efflux, and cuproptosis.
• δAe disrupted CBX7-ATP7A LLPS, restoring ATP7A function and improving cardiac outcomes.
• The δAe-loaded hydrogel demonstrated efficacy in aged mouse and minipig MIR models, improving structural, functional, and electrophysiological parameters.

Conclusions:

• CBX7-mediated cuproptosis is a key mechanism in age-related cardiac dysfunction after MIR.
• δAe, delivered via a multifunctional hydrogel, represents a promising therapeutic strategy for cardiac repair in aging populations.