Cholesterol is an essential lipid molecule that maintains membrane structure, supports hormone synthesis, and regulates cellular signaling. However, its homeostasis must be tightly controlled. A new review by Prof. Zhiguang Su at West China Hospital of Sichuan University, published in Molecular Biomedicine , integrates recent discoveries on the molecular regulation of cholesterol metabolism and its implications for a wide spectrum of human diseases.
The paper outlines four interconnected modules of cholesterol metabolism : hepatic de novo synthesis , intestinal absorption , conversion to bile acids, steroid hormones, and vitamin D, and reverse transport via HDL . These processes are orchestrated by transcriptional regulators such as SREBP2 , LXR, and PPAR, as well as signaling pathways including AMPK , mTOR , and FXR–FGF19. Together, these networks maintain lipid balance in response to nutritional and hormonal c ues.
When the regulatory system of cholesterol metabolism breaks down, it gives rise to a broad spectrum of cholesterol-related cardiometabolic, neurodegenerative, and so on. Excessive cholesterol synthesis or defective efflux promotes atherosclerosis, coronary artery disease, and metabolic-associated fatty liver disease (MAFLD) through lipid accumulation, macrophage foam cell formation, and chronic inflammation. In the nervous system, impaired cholesterol turnover disrupts neuronal membrane composition, impairs synaptic transmission, and hinders amyloid-β clearance, thereby accelerating Alzheimer’s disease and other neurodegenerative conditions. Dysregulated cholesterol metabolism also underlies gallstone formation and contributes to cancer progression through enhanced SREBP2 activity, ACAT-mediated esterification, and abnormal cholesterol signaling.
Beyond statins and PCSK9 inhibitors, the review discusses cutting-edge therapeutic innovations that precisely target cholesterol regulatory circuits. CRISPR-based in vivo gene editing (e.g., VERVE-101 ), siRNA drugs (inclisiran), and monoclonal antibodies against ANGPTL3 , ASGR1 , and Lp(a) exemplify the rise of molecular precision therapy. These interventions offer longer-lasting lipid control and reduced side effects. In parallel, natural products such as berberine and dietary supplements are being explored for their ability to restore cholesterol and bile acid balance via gut–liver axis modulation.
Finally, Zhiguang Su’s team pointed out that cholesterol and its metabolism are fundamental to cellular homeostasis and systemic health, regulating key processes from membrane integrity to steroidogenesis. Despite advances in therapies like statins and gene editing, challenges like residual cardiovascular risk remain. Future research must fill gaps in cholesterol biology to advance precision medicine for cholesterol-related diseases.
See the article:
Cholesterol metabolism: molecular mechanisms, biological functions, diseases, and therapeutic targets
https://doi.org/10.1186/s43556-025-00321-3
Molecular Biomedicine
9-Oct-2025