Emerging Therapies in Hypercholesterolemia: Mechanistic Insight and Key Molecular Inhibitors

Hypercholesterolemia remains a critical global risk factor for cardiovascular disease, necessitating continued innovation in lipid-lowering strategies. Traditional therapies, such as statins and bile acid sequestrants, are effective; however, current treatments have limitations, including side effects and variable responses. Advances in lipid metabolism have enabled the development of novel agents targeting new molecular pathways. This manuscript reviews cholesterol biosynthesis, the pathophysiology and diagnosis of hypercholesterolemia, and current treatment options, with emphasis on the mechanisms of action and therapeutic challenges. It highlights emerging therapies, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. ATP-Citrate lyases inhibitors (e.g., bempedoic acid), and small interfering RNAs (e.g., inclisiram), alongside nutraceuticals and gene–editing strategies. These novel agents modulate low–density lipoprotein cholesterol absorption, transport, and synthesis simultaneously. By outlining current prospective molecular targets, this work aims to inform the next generation of personalized, effective, and sustainable Hypercholesterolemia treatments, paving the way for precision and specific cardiovascular risk management.