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

PMID 42101949 | DOI 10.1097/CRD.0000000000001296 · Cardiology in review · 2026

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Anthracycline-induced cardiotoxicity continues to be a significant clinical challenge in oncology, affecting up to 30% of patients who are subjected to sequential chemotherapy regimens and substantially restricting the therapeutic potential of these highly effective anticancer agents. Despite the fact that anthracycline-based chemotherapy has an overall 5-year survival rate of 80%, dose-dependent cardiotoxicity is a rising safety concern which manifests as cardiomyopathy or congestive heart failure. This highlights the need for novel cardioprotective strategies are required as the currently available regimens are insufficiently effective. Anthracycline exposure induces proprotein convertase subtilisin/kexin type 9 (PCSK9) upregulation in cardiomyocytes in a concentration- and time-dependent manner. The nuclear accumulation induces apoptosis through the degradation of karyopherin subunit beta-1 (KPNB1). Elevated PCSK9 levels are linked to pathological remodeling, increased myocardial fibrosis, and a reduced left ventricular ejection fraction. Cardioprotection against Anthracycline-induced cardiotoxicity is primarily achieved through lipid-independent mechanisms, including the suppression of inflammasome-mediated injury, modulation of innate immune signaling, attenuation of myocardial fibrosis, and restoration of mitochondrial homeostasis, which are regulated by PCSK9 inhibition. The inhibition of PCSK9 has been demonstrated in preclinical models to enhance anticancer efficacy by reducing chemoresistance and increasing cardiomyocyte viability by 35-88% during anthracycline/trastuzumab exposure.