Beyond monoclonal antibodies: a systematic review and meta-analysis of preclinical small-molecule PCSK9 inhibitors

This systematic review aims to identify, characterize, and synthesize the available preclinical evidence on small-molecule modulators of PCSK9. The review focuses primarily on experimental studies conducted in cell-based/in vitro systems and non-human animal models. It evaluates synthetic and naturally derived small molecules capable of modulating PCSK9 expression, activity, secretion, degradation, or its interaction with the low-density lipoprotein receptor (LDLR). The review characterizes the compounds investigated, experimental models, mechanisms of action, doses or concentrations, and reported effects related to PCSK9 and lipid metabolism. A narrative synthesis is used to summarize the available preclinical evidence. Where sufficiently comparable quantitative data are available, particularly for total cholesterol, a meta-analysis is conducted to estimate the magnitude of treatment effects. The review is intended to provide an overview of the current preclinical landscape of small-molecule PCSK9 modulation, identify promising pharmacological strategies, and highlight gaps in the available evidence that may guide future experimental and translational research.