Cholesterol is a very important class of lipid hydrophobic small molecules with important physiological functions. Abnormalities in cholesterol metabolism are strongly associated with metabolic diseases, neurological disorders and tumors. Over the past 200 years, numerous scientific studies related to cholesterol have been awarded with Nobel Prizes; meanwhile, the development and application of a variety of drugs targeting cholesterol-regulating pathways cover a wide range of areas in human medical research and health management, and have broad and long-lasting market prospects.

Cholesterol is a very important life substance, discovered by French and German medical doctors in gallstones in the late 18th century. In 1816, the chemist Michel-Eugène Chevreul named it cholesterine, derived from the Greek words chole (bile) and stereos (solid), meaning " solid bile"; later research found that its structure contains hydroxyl groups, so with the "-ol" ending, the name "Cholesterol", which is still being used today.

It is found that cholesterol not only exists in gallstones, but also exists in all organs of humans and vertebrates, accounting for 0.2% of the total weight of the human body, with more abundant in the nervous system, brain, spinal cord, liver, kidneys and skin.. Cholesterol playsimportant and indispensable roles in animal tissues and cells.

- Cholesterol is an important component of cell membranes, maintaining membrane integrity, regulating membrane fluidity and phase transitions, and regulating cell-cell commumations as well as intra- and extracellular exchange of substances and signals.

- Cholesterol is precursor for the synthesis of bile acids, vitamin D, and steroid hormones (e.g., adrenal hormones and sex hormones).

- Cholesterol is involved in many important intracellular signaling pathways and has important regulatory roles in embryonic development and tumorigenesis.

Abnormalities in cholesterol metabolism are associated with a variety of diseases. For example, high blood cholesterol levels cause hypercholesterolemia, which is closely related to atherosclerosis,  therombus, gallstones, fatty liver disease, coronary disease and stroke. Meanwhile, studies have shown that abnormal cholesterol metabolism is also closely related to neurological diseases and tumors.

-In 1904, Felix Marchand, a German pathologist, observed atherogenic lipids in atherosclerotic plaques and formally proposed "atherosclerosis (atheroslerosis)".

- In 1910, Adolf Windaus, a German chemist, found that the cholesterol content in atherosclerotic lesions was more than 20 times higher than that of healthy people, and hypothesized that its elevation was an important cause of atherosclerosis.

- In 1913, Russian pathologist Nikolai N. Anichkov successfully induced an atherosclerotic phenotype in rabbits fed with high cholesterol diets, clarifying the risk of cholesterol in vascular disease.

- Grigaut (1910) and Autenrieth (1914) developed methods for the analysis of blood and tissue cholesterol, and since then scientists have been conducting systematic research on the role and mechanisms of cholesterol in clinical practices.

- In 1939, Carl Müller, a Norwegian physician, firstly reported familial hypercholesterolemia (FH), which causes  stroke and heart  attack in a population-based survey.

- In 1955, the American nutritionist Ancel Keys led a large-scale epidemiological study, which confirmed that dietary cholesterol is significantly associated with the incidence of cardiovascular disease.

- In 1970, American scientists Michael Brown and Joseph Goldstein isolated LDLR and proved that LDLR deficiency resulted in the body's inability to remove cholesterol from the blood, revealing the genetic cause of familial hypercholesterolemia.

- In 1994, Larry Sparks and others found that high cholesterol diet would increase Aβ deposition in rabbit brain, and that cholesterol might be a potential cause of Alzheimer's disease (AD). In the following 20 years, based on epidemiological as well as basic medical researches, it has been continuously suggested that high cholesterol is associated with AD.

- At the beginning of the 20th century, the scientific community began to pay attention to the association between tumors and cholesterol, and scientific research has gradually shown that cholesterol is closely related to tumorigenesis, metastasis, and tumor immunity, and that cholesterol modulation has become a potential therapeutic tool for tumors.

Cholesterol related studies have spanned centuries and centuries, they have greatly influenced the development of human scientific and medical researches. Scientists have been awarded several Nobel Prizes in Chemistry, Physiology or Medicine for their work on cholesterol.

- German chemist Adolf Windaus was awarded the 1928 Nobel Prize in Chemistry for his pioneering research about sterols, revealing the structure of cholesterol and the relationship between sterols and vitamins.

- German chemist Heinrich Otto Wieland successfully extracted bile acids and revealed their relationship with cholesterol, and preliminarily determined the chemical structure of bile acids. He was awarded the 1927 Nobel Prize in Chemistry.

- Dorothy Mary Crowfoot Hodgkin et al. were awarded the 1964 Nobel Prize in Chemistry for their use of X-ray diffraction to study steroidal compounds and subsequently determined the chemical structures of vitamin D and iodinated cholesterol.

- Adolf Frederick Johann Butenandt et al. were awarded the 1939 Nobel Prize in Chemistry for their successful isolation of sex hormones and determination of their relationship to cholesterol.

- German-American biochemist Konrad Emil Bloch and others used isotope tracer methods to study the cholesterol synthesis pathway. Their work revealed the biosynthetic pathway of cholesterol and provided an effective target in human to target cholesterol regulation and fight against cardiovascular diseases. He was awarded the Nobel Prize in Physiology or Medicine in 1964.  

- American scientists Joseph Goldstein and Michael Brown demonstrated that the low-density lipoprotein receptor (LDLR) mediates the transport of cholesterol from the blood to the cells, and that abnormalities in the expression or function of the LDLR cause cholesterol accumulation in the blood, leading to hypercholesterolemia and atherosclerotic cardiovascular disease.. This study revealed the cause of familial hypercholesterolemia and provided new ideas for the treatment of atherosclerotic cardiovascular disease. They  were awarded the 1985 Nobel Prize in Physiology or Medicine.

Traditional cholesterol-lowering drugs mainly include statins, bile acid sequestrants, cholesterol-absorption inhibitors and so on. In recent years, with the emergence of new targets such as PCSK9 and the new research and development applications, new anti-cholesterol drugs carry people's attention.

- In 1978, statin was launched on the market. This drug competitively inhibits HMGCR to reduce cholesterol synthesis; at the same time, it increases the activity of LDLR and accelerates the reduction of LDL-C level, which is the most widely used cholesterol-lowering drug in clinic. However, statin resistance and its side effects are important factors plaguing the therapeutic effect, greatly limiting the therapeutic effect of statin and the patient population.

- In 2002, ezetimibe was launched on the market. This drug selectively inhibits cholesterol transporter protein in the small intestine, effectively reducing intestinal cholesterol absorption and lowering blood and liver cholesterol levels. The drug is usually used in combination with a statin, meanwhile the therapeutic effect is limited in populations.

- In 2015 and 2020, monoclonal antibodies and siRNA drugs for the preprotein convertase cholestrol 9 (PCSK-9) were marketed. These drugs effectively reduce blood cholesterol levels by enhancing LDLR clearance of blood LDL cholesterol. However, PCSK9 monoclonal antibodies need to be used in combination with statin, and due to the safety considerations from the regulatory authorities, insurance companies limit the population of the patients, and theclinical application is limited due to the high price.

- In 2020, Bempedoic acid was launched. The drug competes to inhibit citrate lyase (ACL), inhibiting cholesterol synthesis and lowering LDL-C. In 2021, Evinacumab was launched. This drug is a monoclonal antibody to angiopoietin-like 3 (ANGPTL3), and inhibition of ANGPTL3 function is associated with lower plasma triglyceride and LDL-C levels. The clinical performance and market prospects of the novel drug remain to be further evaluated.

- Due to the aging of the population and the youthfulness of the disease, the demand for lipid-lowering drugs is also growing; the diagnosis and treatment rate of patients is low, so there is a great potential in the stock market of medication; the increasing emphasis on the prevention and treatment of chronic diseases in China promotes the expansion of the demand for lipid-lowering drugs in the market. The size of the pharmaceutical market for cholesterol-related diseases is expected to continuously grow.

- Although a variety of lipid-lowering drugs such as statin are available in the market, rate of drug resistance will continuously increase in the foreseeable future, and to develop new lipid-lowering drugs is still taking a long way to go.