Janus Hydrogels Delivering Low-Density Lipoprotein Receptor-Related Protein 6 Inhibitor Enhance Myocardial Repair via m6A-Dependent Cuproptosis in Bama Pigs

Area of Science:

• Cardiovascular Biology
• Cell Death Mechanisms
• Biomaterials

Background:

• Copper overload triggers cuproptosis, a unique cell death pathway, through mitochondrial reactive oxygen species (ROS).
• Myocardial infarction (MI) leads to elevated copper levels in cardiac tissue, sensitizing cardiomyocytes to copper toxicity.
• Low-density lipoprotein receptor-related protein 6 (LRP6) activation exacerbates copper toxicity by regulating ferredoxin 1 (FDX1) and facilitating copper influx.

Purpose of the Study:

• To elucidate the role of LRP6 in copper-induced cell death (cuproptosis) following myocardial infarction (MI).
• To identify therapeutic agents targeting LRP6 to mitigate cuproptosis and preserve cardiac function.
• To develop an advanced drug delivery system for potential MI treatment.

Main Methods:

• Investigated the interaction between LRP6, ALKBH5, and FDX1 in cardiomyocytes under copper overload.
• Utilized high-throughput screening to identify LRP6 inhibitors, leading to the discovery of chrysin-7-O-glucuronide (C7Og).
• Developed a Janus hydrogel incorporating C7Og and benzalkonium chloride-modified tannic acid for myocardial patching.

Main Results:

• LRP6 activation suppresses FDX1 m6A modification and enhances copper influx, promoting cuproptosis in cardiomyocytes.
• C7Og effectively inhibits LRP6, mitigating cuproptosis without impairing beneficial cardiac functions.
• The C7Og-loaded Janus hydrogel myocardial patch significantly reduced infarct size and improved cardiac function in rat and pig models.

Conclusions:

• LRP6 is a critical mediator of copper toxicity and cuproptosis in the context of MI.
• C7Og represents a promising therapeutic candidate for preventing LRP6-driven cell death in cardiac injury.
• The developed hydrogel-based myocardial patch demonstrates strong translational potential for treating myocardial infarction.