Traditional Chinese medicine targets cholesterol metabolism for cancer treatment

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Mar 31 2025

Traditional Chinese medicine offers promising natural compounds that modulate cholesterol metabolism, unveiling new therapeutic pathways for cancer treatment.

Study: Targeting cholesterol metabolism: A promising therapy strategy for cancer. Image Credit: Light Stock / Shutterstock.com

In a recent study published in Acta Pharmacologica Sinica, researchers review the four major cholesterol metabolism processes and how natural products used in traditional Chinese medicine (TCM) may modulate cholesterol metabolism for cancer treatment.

The role of cholesterol in cancer

Within the cell membrane, cholesterol, an amphiphilic sterol molecule, maintains the integrity of this structure by supporting its fluidity, while also regulating ion channel function and membrane protein organization. Cholesterol homeostasis is achieved by maintaining a balanced cholesterol de novo biosynthesis, uptake, efflux, and esterification.

Cholesterol also supports tumor cell proliferation by regulating signal transduction and membrane biogenesis. Previous studies have reported that alterations in cholesterol homeostasis are implicated in the progression of cancer. For example, high expression of adenosine triphosphaste (ATP)-binding cassette transporter A1 (ABCA1) leads to cholesterol efflux and increases membrane fluidity, which contributes to triple-negative breast cancer (TNBC) metastasis.

Existing therapeutics that target cholesterol metabolism, including certain enzyme inhibitors and transport protein modulators, have been investigated for their potential anti-neoplastic effects. However, these treatments are associated with limited long-term efficacy in certain patient populations, as well as an increased risk of adverse side effects and drug resistance.

Thus, there remains an urgent need to identify novel therapeutic approaches that can overcome these challenges. TCM, for example, which are typically well-tolerated natural products, have been studied for their ability to regulate cholesterol metabolism for the treatment of cancer.

In fact, one recent study reported that TCM-derived compounds like quercetin can reduce cholesterol synthesis by activating adenosine monophosphate-activated protein kinase (AMPK) and inhibiting 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) activity.

Targeting cholesterol biosynthesis

The majority of cells, except mature red blood cells and brain tissue, can synthesize cholesterol. Cholesterol synthesis is an ATP-intensive process that involves nearly thirty enzymatic reactions and over fifteen proteins; therefore, any disruptions in genes or enzymes involved in cholesterol homeostasis can promote cancer.

Sterol-regulatory element binding protein 2 (SREBP2), 3-hydroxy-3-methylglutaryl conenzyme A reductase (HMGCR), and squalene epoxidase (SQLE) are key molecules involved in cholesterol biosynthesis, which can be inhibited through natural products.

For example, SREBP2 can be targeted by artesunate (ART), which is a derivative of artemisinin, to inhibit cholesterol synthesis. Gypenoside L can also regulate the methyl valproate (MVA) pathway by targeting SREBP2, which mediates cholesterol biosynthesis and supports hepatic tumor stem cell growth.

Natural products, such as emodin extracted from the roots of Reynoutria japonica and osthole, which is obtained from Cnidium monnieri, synergistically reduce SREBP2 activity by their involvement in the nuclear factor κB (NF-κB), mitrogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt). However, additional research is needed to elucidate their precise mechanism of action.

Alpineisoflavone (AIF) also exhibits anticancer properties through its ability to inhibit androgen receptor (AR) expression, thereby targeting HMGCR-mediated cholesterol biosynthesis.

Targeting cholesterol uptake

Cancer cells rely on exogenous cholesterol uptake to support rapid proliferation. This uptake is mediated by proteins such as niemann-pick type C1-like 1 (NPC1L1) and low-density lipoprotein receptor (LDLR). However, ezetimibe, which is an approved NPC1L1 inhibitor that is typically used to treat hypercholesterolemia, is associated with limited anti-cancer efficacy.

Curcumin, a natural compound extracted from turmeric, exhibits activity against lung, breast, and colorectal cancers. These anti-cancer effects are attributed to increased intracellular cholesterol transport, a process that relies on transient receptor potential A1 (TRPA1) activation. Circumin also decreases SREBP2 and NPC1L1 levels in a dose-dependent manner.

Isoglycyrrhizin is a chalcone-structured flavonoid extracted from Glycyrrhiza uralensis that downregulates NPC1L1 expression and completely inhibits cholesterol uptake with negligible cytotoxicity. Despite these observations, additional in vivo experiments are needed to determine its safety and efficacy.

Chrysanthemone is a potent NPC1L1 inhibitor extracted from Tanacetum parathenium. To date, the anti-cancer activity of chrysantemone remains unclear.

Targeting cholesterol efflux

Multiple studies have demonstrated the role of ABC transporter and liver X receptor (LXR) in cholesterol efflux. These studies have also revealed the effectiveness of small molecules to enhance these processes to achieve anticancer effects.

Celastrol, a triterpenoid compound extracted from Tripterygium wilfordii, exhibits anti-cancer activity by inhibiting the growth of clear cell renal carcinoma (ccRC) xenograft tumors in a dose-dependent manner. Celastrol also upregulates ABCA1 expression in tumor tissues, which promotes cholesterol efflux by enhancing lipid metabolism and reducing cholesterol accumulation within tumor cells.

Targeting cholesterol esterification

Cholesterols are converted to cholesteryl esters (CEs) by acyl-coenzyme A and cholesterol acyltransferase (ACAT). The accumulation of CEs provides tumor cells with an abundance of cholesterol for maintaining membrane formation, fluidity, and stability. CE acumination is also associated with the loss of the tumor suppressor factor phosphatase and tensin homolog (PTEN).

Manzamine A is another bioactive compound that targets ACAT2 to inhibit cholesterol esterification, thereby promoting anticancer activity. Recent in vivo studies using a murine melanoma model confirmed the role of avasimibe as an ACAT inhibitor that reduces CEs levels to promote anti-cancer effect.