Arch Microbiol. 2026 Jun 22;208(9):453. doi: 10.1007/s00203-026-05006-1.
ABSTRACT
From the perspective of both the host cell and the virus, cholesterol (CHO) plays a critical role during viral infection. Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases the risk of cardiovascular disease by regulating plasma levels of lipoprotein(a), triglyceride-rich lipoproteins, and low-density lipoprotein cholesterol (LDL-C), and by promoting the degradation of the LDL receptor (LDLR). Emerging evidence implicates PCSK9 in the pathophysiology of several viral diseases, including human immunodeficiency virus (HIV), SARS-CoV-2, dengue virus (DENV), and hepatitis viruses. Two monoclonal antibody PCSK9 inhibitors (PCSK9i), evolocumab (Repatha®) and alirocumab (Praluent®), are approved by the Food and Drug Administration (FDA) for managing atherosclerotic risk. However, despite preclinical studies suggesting that these inhibitors and other CHO-lowering medications may interfere with viral replication, their therapeutic application as antivirals remains limited due to various restrictions. Naturally occurring compounds such as curcumin, berberine, quercetin, and polyphenols have demonstrated PCSK9-modulating and antiviral properties in preclinical models against viruses including HIV, hepatitis viruses, SARS-CoV-2, DENV, herpes simplex virus, human cytomegalovirus, and Epstein-Barr virus. Crucially, the majority of evidence for these natural substances remains preclinical, derived from in vitro and animal studies. The contribution of PCSK9 inhibition to the reported antiviral effects remains unclear, as pleiotropic mechanisms may be involved. Therefore, rather than being clinically proven substitutes for licensed PCSK9-targeted treatments, these molecules should be considered experimental or maybe supplementary medicines. This review examines the current preclinical evidence for natural inhibitors of PCSK9 and their antiviral properties, discusses clinical assessments to date, and considers the potential future role of naturally occurring PCSK9i in antiviral development, acknowledging the substantial research gaps that remain.
PMID:42329435 | DOI:10.1007/s00203-026-05006-1