Protein Targets and the Roles of Natural Compounds in the Treatment and Management of Hypercholesterolemia: A Comprehensive Review

Hypercholesterolemia, a condition characterized by elevated cholesterol levels, has been identified as a major risk factor for cardiovascular disease, which is recognized as the leading cause of mortality on a global scale. Whereas statins remain the cornerstone of pharmacological treatment for hypercholesterolemia, their long-term use is often limited by side effects such as myopathy and hepatotoxicity. Natural bioactive compounds derived from medicinal plants and foods have emerged as promising alternatives for treating hypercholesterolemia due to their multi-target mechanisms, reduced side effects, and wide availability. These compounds, including polyphenols, flavonoids, terpenoids, and plant sterols, have demonstrated efficacy in regulating major cholesterol metabolic pathways, such as reducing intestinal cholesterol absorption, inhibiting cholesterol synthesis, regulating transcription factors, and increasing cholesterol excretion. This review discusses the molecular mechanisms through which previous natural compounds regulate cholesterol homeostasis, focusing on their interactions with proteins such as HMGCR, NPC1L1, PCSK9, and the transcription factor SREBP-2.