Therapeutic Advances in Sterol Metabolism Review

Abstract

The metabolism of sterol regulates the cholesterol homeostasis, which is used as a dominant therapeutic target in cardiovascular, neurodegenerative and malignancy disorders. The emerging observations show that sterol pathway modulation, specifically, leads to high clinical success. Newer PCSK9 inhibitors, such as inclisiran (small interfering RNA) produce long-lasting LDL-cholesterol lowering (58%) and major adverse cardiovascular event reduction (23 percent) among patients with manifestations in high-risk patients via semi-annual injections. Neurodegenerative strategies involving the activation of the CYP46A1 enzyme by repurposed Efavirenz increase the levels of 24S-hydroxycholesterol levels, leading to amyloid-b clearance and an improvement in the cognitive scores of patients with early-stage Alzheimer disease. At the same time, SOAT1 inhibitors remove cholesterol esters in tumors, which triggers ferroptosis and leads to the suppression of hepatocellular carcinoma growth by 67%. New strategies impending are nuclear receptor modulation with Liver X receptor agonists that stimulate reverse cholesterol transport and reduce atherosclerosis in primates. Possible nutritional interventions comprise intake of plant sterols (2.5 g/day) to lower LDL-C by 12 per cent because they are competitively absorbed by the intestines, and ketogenic diets, to raise neuroprotective 24S-hydroxycholesterol by 40 per cent. Agents of resistance overcoming such as CYP27A1 inhibitors overcome resistance in breast cancer and reconvert the situation to that of re-signifying the cancer cells to chemo-sensitivity. The challenges that still persist include tissue specificity, off-target effect, i.e., diabetes risk with PCSK9 inhibitors, and tumor metabolic plasticity. Recent opportunities are the CRISPR-Cas9 edited LDL receptor with the 89 percent efficiency in familial hypercholesterolemia and nanoparticle-supported blood-brain barrier crossing using oxysterols. Such developments have rendered sterol metabolism an excellent therapeutic target with life-changing potential spanning the cardiovascular, neurological, and oncological disease trajectory, between molecular knowledge and clinical practice, through novel targeting approaches and personalized approaches.

Keywords: 

PCSK9 inhibitors, Oxysterol-based Therapeutics, Cholesterol Homeostasis modulation, SOAT1 Inhibitors, CYP46A1 Brain-Targeted therapy, Ferroptosis Induction, Novel Drug Delivery Systems.