PCSK9 as a Biomarker and Therapeutic Target for Anthracycline Cardiotoxicity Prevention: Recent Advancements and Future Perspectives

Area of Science:

• Oncology
• Cardiology
• Molecular Biology

Background:

• Anthracycline chemotherapy, while effective against cancer, causes dose-dependent cardiotoxicity, leading to heart failure and limiting treatment.
• Current cardioprotective strategies are insufficient, necessitating novel approaches.

Purpose of the Study:

• To investigate the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in anthracycline-induced cardiotoxicity.
• To evaluate the potential of PCSK9 inhibition as a cardioprotective strategy.

Main Methods:

• Examined the effect of anthracycline exposure on PCSK9 levels in cardiomyocytes.
• Investigated the molecular mechanisms linking PCSK9 nuclear accumulation to apoptosis via karyopherin subunit beta-1 (KPNB1) degradation.
• Assessed the impact of PCSK9 inhibition on lipid-independent cardioprotective pathways and anticancer efficacy in preclinical models.

Main Results:

• Anthracycline exposure upregulates PCSK9 in cardiomyocytes in a time- and concentration-dependent manner.
• Elevated PCSK9 is associated with pathological cardiac remodeling, fibrosis, and reduced ejection fraction.
• PCSK9 inhibition demonstrated cardioprotection by suppressing inflammasome injury, modulating immune signaling, reducing fibrosis, and restoring mitochondrial function.
• Inhibition of PCSK9 enhanced anticancer efficacy and increased cardiomyocyte viability by 35-88% during anthracycline/trastuzumab exposure in preclinical models.

Conclusions:

• PCSK9 plays a critical role in anthracycline-induced cardiotoxicity through mechanisms involving KPNB1 degradation and apoptosis.
• Targeting PCSK9 offers a promising therapeutic strategy for mitigating cardiotoxicity and potentially enhancing the efficacy of anthracycline-based chemotherapy.