Research progress on cholesterol metabolism and tumor therapy

Abstract

Cholesterol and its metabolic derivatives have important biological functions and are crucial in tumor initiation, progression, and treatment. Cholesterol maintains the physical properties of cellular membranes and is pivotal in cell signal transduction. Cholesterol metabolism includes both de novo synthesis and uptake from extracellular sources such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL). This review explores both aspects to provide a comprehensive understanding of their roles in cancer. Cholesterol metabolism is involved in bile acid production and steroid hormone biosynthesis and is closely linked to the reprogramming of endogenous and exogenous cellular signals within the tumor microenvironment. These signals are intricately associated with key biological processes such as tumor cell proliferation, survival, invasion, and metastasis. Evidence suggests that regulating cholesterol metabolism may offer therapeutic benefits by inhibiting tumor growth, remodeling the immune microenvironment, and enhancing antitumor immune responses. This review summarizes the role of cholesterol metabolism in tumor biology and discusses the application of statins and other cholesterol metabolism inhibitors in cancer therapy, aiming to provide novel insights for the development of antitumor drugs targeting cholesterol metabolism and for advances in cancer diagnosis and treatment.

Keywords: Cholesterol metabolism; Clinical application; Therapy; Tumorigenesis.

Fig. 1

Overview of the remodeling mechanisms of cholesterol metabolism. Cholesterol metabolic reprogramming refers to the process by which cells, particularly cancer cells, adaptively regulate cholesterol synthesis, uptake, storage, and utilization to meet the demands of rapid growth and survival. Tumor cells enhance de novo cholesterol synthesis through upregulated HMGCR activity and increase cholesterol uptake by overexpressing LDLR. SR-B1 selectively mediates the uptake of HDL-derived cholesteryl esters into cells and tissues, helping to regulate plasma membrane cholesterol levels. Excess cholesterol is stored as cholesteryl esters in lipid droplets via ACAT enzymes, providing a reservoir for metabolic needs. Simultaneously, cholesterol efflux is suppressed by downregulating transporters such as ABCA1 and ABCG1, leading to intracellular cholesterol accumulation that supports membrane structure, lipid raft formation, and oncogenic signaling pathways like PI3K/AKT. Cholesterol derivatives, including oxysterols and steroid hormones, further influence the tumor microenvironment by modulating immune suppression and promoting cell growth. This reprogramming is tightly controlled by factors such as SREBP2 and LXRs and can also be influenced by non-coding RNAs and inflammatory signals. In addition, SCAP interacts with INSIG1 to regulate the activation of SREBP2 to control cholesterol synthesis. Understanding cholesterol metabolic reprogramming sheds light on its role in cancer progression, immune evasion, and therapeutic resistance, offering potential targets for novel cancer treatments, such as HMGCR inhibitors, LDLR blockers, and cholesterol efflux modulators

Fig. 2

Overview of cholesterol metabolism and tumor drug resistance. In various cancers, to address chemotherapy resistance, a common approach involves inhibiting the mevalonate metabolic pathways, thereby reducing intracellular cholesterol levels. This strategy often includes combining inhibitors of genes associated with cholesterol biosynthesis with anticancer drugs