---
title: "Cholesterol in Hematological Malignancies: Metabolism, Mechanisms, and Clinical Implications"
id: "frontiers-in-immunology-3-cholesterol-in-hematological-malignancies-metabolism-mechanisms-and-clinical"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-3-cholesterol-in-hematological-malignancies-metabolism-mechanisms-and-clinical"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1947729"
published_at: "2026-09-21T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Cholesterol in Hematological Malignancies: Metabolism, Mechanisms, and Clinical Implications
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-3-cholesterol-in-hematological-malignancies-metabolism-mechanisms-and-clinical
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1947729)
- **Published At:** 2026-09-21T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Cholesterol is an amphiphilic lipid essential for membrane structure, lipid-raft function, precursor synthesis (steroid hormones, bile acids, vitamin D), and signaling; intracellular levels are tightly regulated by synthesis, uptake, efflux, conversion, and trafficking. - Clinical studies show **hypocholesterolemia** frequently accompanies hematological malignancies and may precede diagnosis by years, correlating with disease onset, progression, treatment response, and outcomes. - Tumor-associated hypocholesterolemia likely arises from combined mechanisms: altered lipoprotein metabolism, liver dysfunction from systemic inflammation, and aberrant tumor cell uptake/efflux of cholesterol. - Cholesterol biosynthesis primarily follows the mevalonate (MVA) pathway; HMGCR and SQLE are key rate-limiting enzymes. Dietary absorption via NPC1L1 and intracellular esterification by ACAT2 are important exogenous routes. - Systemic clearance occurs through HDL-mediated reverse cholesterol transport (ABCA1/ABCG1, LCAT, SR-BI) and LDLR-mediated hepatic uptake; these pathways determine plasma cholesterol distribution among FC and CE. - Cholesterol organizes lipid rafts that support receptor clustering and signaling (PI3K/Akt, Hedgehog/SMO-GLI, TCR, LRP8/mTORC1). Altered cholesterol homeostasis in tumors promotes proliferation, stemness, therapy resistance, T-cell dysfunction, and macrophage M2-like polarization. - Transcriptional control by **SREBP** family (notably **SREBP2**) and **LXR** isoforms (LXRα/β) forms a feedback circuit: SREBP2 induces cholesterol synthesis/uptake (HMGCR, LDLR), LXRs induce efflux (ABCA1/ABCG1). Hematologic malignancies exploit this axis—upregulating SREBP2 targets and suppressing LXR-driven efflux—to sustain cholesterol supply. - Cell-type–specific effects: SREBP supports T-cell lipid-raft integrity and HSC self-renewal; LXR influences macrophage anti-inflammatory programs; dysregulation contributes to immune escape and preleukemic evolution. - The review outlines metabolism, molecular mechanisms, tumor and immune effects, and therapeutic strategies targeting cholesterol metabolism; the provided source excerpt stops during the section summarizing cholesterol levels across malignancy subtypes, so some clinical detail and tables were not reported in the supplied text.
## Clinical Analysis & Structured Key Points
Frontiers | Cholesterol in hematological malignancies: metabolism, mechanisms, and clinical implications REVIEW article Front. Immunol. , 21 September 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1947729 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Editor & Reviewers Edited by T S Tao Sun Reviewed by J J Jianxin Jiang Z L Zhao Li Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Figure 5 View in article Table 1 Cholesterol levels in hematological malignancies and clinical correlation. View in article Table 2 Agents targeting cholesterol metabolism in hematological malignancies. View in article REVIEW article Front. Immunol. , 21 September 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1947729 Cholesterol in hematological malignancies: metabolism, mechanisms, and clinical implications Y Z Yaqin Zhang 1 M Y Mengbo Yang 1 S Y Siyuan Yan 2 R L Ruiyang Li 1 Y Z Yuanjun Zheng 3 D Z Donglei Zhang 4 H S Hongyuan Shang 5 * F W Fang Wei 3 * 1. The First Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China 2. Precision Medicine Laboratory for Chronic Non-Communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining, China 3. Department of Hematology, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China 4. Department of Ophthalmology, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China 5. College of Pharmacy, Shanxi Medical University, Taiyuan, China See more Article metrics View details Abstract Cholesterol is an amphiphilic molecule that is essential for maintaining membrane structure and integrity, serves as a precursor for steroid hormone synthesis, and plays a critical role in metabolic homeostasis and physiological function. In recent years, dysregulated cholesterol metabolism has emerged as a major focus of research in the field of hematological malignancies. A growing body of clinical evidence indicates that hypocholesterolemia is a common concomitant condition in various hematological malignancies and is closely associated with disease onset, progression, therapeutic response, and clinical outcomes. The mechanisms underlying tumor-associated hypocholesterolemia are complex and likely involve dysregulation of lipoprotein metabolism, liver dysfunction caused by systemic inflammatory responses, and abnormal cholesterol uptake and efflux by tumor cells, which collectively contribute to the exacerbation of hypocholesterolemia. In turn, this metabolic signature not only promotes tumor cell proliferation and enhances the potential for therapy resistance, but also reprograms the immune microenvironment by inducing T cell dysfunction and M2-like macrophage polarization. Emerging therapeutic strategies targeting cholesterol metabolism have shown promise in preclinical models. By providing a theoretical foundation, these strategies offer potential avenues for improving the early diagnosis and risk stratification of hematological malignancies and for developing innovative treatment regimens. In this review, we outline the biosynthesis, uptake, excretion, transformation, and regulatory networks of cholesterol; describe the specific alterations in cholesterol levels across different subtypes of hematological malignancies; elucidate the molecular mechanisms underlying hypocholesterolemia; and explore its effects on tumor cell biology and the immune microenvironment, as well as its clinical significance, with the aim of providing new perspectives for related treatment strategies. 1 Introduction Tumor cells undergo metabolic reprogramming to meet the biosynthetic and bioenergetic demands of carcinogenesis. Cholesterol, a major component of the cell membrane, plays a critical role in maintaining membrane integrity and fluidity, facilitating the formation of membrane microdomains, and supporting cellular structure and proliferation ( 1 ). In addition, it not only serves as a precursor for the synthesis of bile acids, vitamin D, and steroid hormones ( 2 ), but also acts as a covalent protein modifier, thereby contributing to a wide range of biological processes. Intracellular cholesterol metabolic homeostasis is maintained by a complex regulatory network governing biosynthesis, uptake, efflux, conversion, esterification, and trafficking ( 3 ). Previous studies have shown that alterations in lipid metabolism are associated with the development of certain cancers ( 4 ). Evidence indicates that serum cholesterol levels begin to decline up to six years prior to the clinical detection of colon cancer and chronic myeloid leukemia ( 5 ), suggesting that cholesterol levels may serve as a predictive marker for early carcinogenesis. Over the past decade, an increasing number of studies have demonstrated that dysregulated lipid metabolism, particularly alterations in cholesterol homeostasis, is closely associated with the initiation, progression, and prognosis of hematological malignancies. In-depth investigation of the mechanistic role of cholesterol in these tumors not only promises to elucidate novel pathogenic mechanisms and provide new biomarkers for early diagnosis and risk stratification, but also establishes a theoretical foundation for the development of innovative therapeutic strategies. These may include targeted agents directed against key nodes within the cholesterol metabolic pathway. Such investigations hold substantial clinical significance and considerable translational potential. 2 Cholesterol: structure, function, and homeostatic regulation The mechanisms underlying cholesterol homeostasis are complex and are regulated through the integration of four key metabolic processes: synthesis, absorption, transformation, and clearance ( Figure 1 ). This coordinated metabolic cycle ensures that cholesterol fulfils its essential roles in membrane structure, signal transduction, and systemic homeostasis. Figure 1 An overview of cholesterol homeostasis (Created in BioRender ). In intestinal epithelial cells, cholesterol is taken up via NPC1L1 and effluxed by ABCG5/G8, while ACAT2 converts it into cholesteryl esters (CE) for chylomicron (CM) formation. De novo synthesis begins with acetyl-CoA and involves HMGCR and SQLE. In the circulation, lipoproteins (VLDL, LDL, HDL) mediate cholesterol transport; LDLR facilitates clearance, while ABCA1 and ABCG1 promote cholesterol efflux to HDL. Macrophages may become foam cells upon cholesterol accumulation. Cholesterol is also converted into bile acids (via CYP7A1), steroid hormones, vitamin D, and oxysterols such as 7α-hydroxycholesterol and 27-hydroxycholesterol. Lysosomal trafficking and glucosylation (ABCG5/G8) further regulate sterol distribution. 2.1 Classification and structure of cholesterol Cholesterol (molecular formula: C27H46O) is a cyclopentane-polyhydrophenanthrene derivative. It consists of three six-membered rings (A, B, and C) fused to a five-membered ring (D). The molecule contains a 3β-hydroxyl group at the C3 position and a double bond between the C5 and C6 positions, with an eight-carbon alkyl side chain attached at the C17 position. It is an amphiphilic molecule that serves as a key structural component of cell membranes and as a precursor for steroid hormones ( 6 ). In plasma, cholesterol exists as free cholesterol (FC, approximately 30%) and cholesteryl esters (CE, approximately 70%), which are formed through esterification catalysed by Lecithin-Cholesterol Acyltransferase (LCAT). These esters are hydrophobic and reside within the core of lipoproteins ( 2 ). Based on their lipoprotein carriers, cholesterol is classified into chylomicrons (CM), very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) ( 4 , 7 ). 2.2 Cholesterol biosynthesis Cholesterol biosynthesis occurs in most mammalian cells, with endogenous synthesis in the liver and dietary absorption representing the two principal sources of cholesterol in the human body ( 8 ). Under physiological conditions, endogenous synthesis predominantly takes place in the liver, where acetyl-CoA is converted into cholesterol through nearly 30 enzymatic reactions, including the mevalonate (MVA) pathway and subsequent squalene biosynthesis ( 9 , 10 ). Among the enzymes involved, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) and squalene epoxidase (SQLE) are key rate-limiting enzymes that catalyse the reduction of HMG-CoA to MVA and the epoxidation of squalene to 2,3-epoxysqualene, respectively ( 11 ). 2.3 Cholesterol absorption In addition to biosynthesis, dietary absorption and subsequent uptake of cholesterol from the circulation play crucial roles in maintaining cholesterol homeostasis. The exogenous absorption of cholesterol is a multi-step process coordinated by multiple proteins. Cholesterol derived from food and bile, following hydrolysis and micellisation, is absorbed by intestinal epithelial cells primarily via Niemann-Pick C1-Like 1 (NPC1L1). Through a series of processes, free cholesterol taken up by NPC1L1 is esterified by cholesterol acyltransferase 2 (ACAT2) in the endoplasmic reticulum and subsequently transported into the circulation in the form of chylomicrons, ultimately being assimilated by the liver ( 12 , 13 ). Conversely, unesterified free cholesterol is actively transported into the intestinal lumen by the heterodimeric ATP-binding cassette (ABC) transporters G5/G8 (ABCG5/G8), thereby limiting net absorption. Furthermore, under conditions of low cholesterol, NPC1L1 can recycle back to the cell membrane to sustain cholesterol uptake ( 14 ). Ultimately, cholesterol is taken up and utilised by the liver and peripheral tissues through receptor-mediated mechanisms, primarily involving the low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SR-BI), thereby serving as a source of exogenous cholesterol for the body ( 15 ). Key proteins at each stage, including NPC1L1, LDLR, and SR-BI, play central roles in maintaining cholesterol homeostasis ( 1 , 16 ). While most mammalian cells obtain cholesterol via endogenous or exogenous uptake ( 17 ), certain specialised cells, such as intestinal epithelial cells and hepatocytes, have additional cholesterol sources, including direct absorption from the intestinal tract and bile via the cholesterol transporter NPC1L1 ( 18 ). 2.4 Cholesterol conversion and clearance As a key metabolic precursor, cholesterol can be converted into a variety of bioactive molecules with important physiological functions across multiple tissues. In the liver, cholesterol is converted into bile acids predominantly via the classical pathway (accounting for > 90% of total conversion). This pathway is initiated by the rate-limiting enzyme cytochrome P450 family 7 subfamily A member 1 (CYP7A1), which catalyses the conversion of cholesterol to 7α-hydroxycholesterol; this intermediate is subsequently converted to C4, ultimately leading to the synthesis of cholic acid and chenodeoxycholic acid ( 19 ). When the classical pathway is impaired or under metabolic stress, an alternative pathway initiated by CYP27A1 generates 27-hydroxycholesterol, which is further catalysed by CYP7B1 to supplement the production of chenodeoxycholic acid ( 20 ). Intracellularly, cholesterol can be converted into cholesterol glucoside by UDP-glucose:sterol glucosyltransferase, thereby contributing to membrane stability and immune modulation ( 21 ). In the skin, 7-dehydrocholesterol is converted into active vitamin D3 following UVB exposure and subsequent two-step hydroxylation in the liver and kidneys ( 22 ). In the adrenal cortex, cholesterol is converted into pregnenolone by CYP11A1 and is subsequently synthesised into steroid hormones. Systemic clearance of cholesterol is primarily achieved through two pathways: HDL-mediated reverse cholesterol transport and LDL-mediated hepatic uptake ( 23 ). During reverse cholesterol transport, nascent HDL is assembled from apolipoprotein A-I (ApoA-I) and phospholipids ( 24 ). It acquires free cholesterol from peripheral cells, such as macrophages, via ABCA1/ABCG1; this cholesterol is then esterified by LCAT to form mature HDL particles ( 25 ). These cholesteryl esters are either selectively taken up by hepatocytes via SR-BI or transferred to apolipoprotein B-containing lipoproteins (such as LDL and VLDL) via Cholesteryl Ester Transfer Protein (CETP), and are ultimately cleared through the LDLR-mediated hepatic pathway. In the LDL clearance pathway, LDL particles bind to LDLR on the surface of hepatocytes via apolipoprotein ApoB-100 ( 26 ). Following internalisation, cholesteryl esters are hydrolysed into free cholesterol, while LDLR is recycled back to the cell membrane to maintain uptake capacity. 2.5 Biological functions and signaling-regulatory roles of cholesterol Cholesterol is a multifunctional molecule essential for maintaining membrane integrity and fluidity, accounting for 20-30% of membrane lipids. It is embedded within the phospholipid bilayer, where it buffers membrane phase transitions, preventing excessive fluidity at high temperatures and the formation of rigid, gel-like structures at low temperatures ( 27 ). In addition to this structural role, cholesterol forms lipid raft microdomains in association with sphingolipids, which serve as platforms for signal transduction, receptor activation, and immunocontact formation ( 28 , 29 ). Cholesterol serves as the universal precursor for all steroid hormones ( 30 ). Through the action of the rate-limiting enzyme CYP11A1 (cholesterol side-chain cleavage enzyme) ( 31 ), cholesterol is converted into pregnenolone, which is subsequently synthesised into mineralocorticoids, glucocorticoids, and sex hormones, thereby regulating electrolyte balance, stress responses, and reproductive physiology ( 30 ). Furthermore, cholesterol acts as a vital modulator of cellular signaling pathways. It regulates ion channel functions through specific mechanisms ( 32 ), and directly binds to Patched-1 (PTCH1) and Smoothened (SMO) to modulate Hedgehog signaling and precisely control developmental and homeostatic processes ( 33 ). The dysfunction of cholesterol-dependent signaling networks facilitates the progression of hematologic malignancies. Cholesterol preserves the structural integrity of lipid rafts to sustain normal PI3K/Akt signaling transduction ( 34 , 35 ). Its deficiency induces adaptive survival programs in tumor cells and ultimately leads to chemotherapy resistance. Upon activation, SMO signals to downstream GLI transcription factors. This signaling axis maintains the self-renewal of leukemia stem cells ( 36 ) and exerts oncogenic functions in multiple myeloma and lymphoma ( 37 ). Cholesterol metabolism modulates TCR complex assembly to alleviate T cell exhaustion and cross-regulates the mTORC1 signaling pathway ( 38 – 40 ). LRP8-mediated cholesterol metabolism further controls mTORC1 activity and tumor cell apoptosis in multiple myeloma ( 41 ). In conclusion, cholesterol serves as a core mediator linking metabolic reprogramming and oncogenic signaling. It plays a crucial pathological and clinical role in the progression, immune escape and treatment resistance of hematologic malignancies ( Figure 2 ). Figure 2 Cholesterol-regulated signal transduction axes in hematological malignancies (Created in BioRender ). Cholesterol is embedded in plasma membrane lipid rafts, where it regulates receptor clustering (e.g., PTCH1, SMO, LRP8) and modulates key downstream signaling cascades, including the Hedgehog/GLI, PI3K/Akt, TCR, and LRP8/mTORC1 axes. Under physiological conditions, these pathways coordinate normal T-cell activation, survival homeostasis, and antitumor immunity. However, cholesterol deficiency or metabolic reprogramming disrupts these networks, driving leukemia stem cell self-renewal, promoting myeloma/lymphoma progression, inducing T-cell exhaustion and immune evasion, and ultimately conferring chemotherapy resistance and adverse clinical outcomes. Solid arrows, T-bars, and dashed lines indicate activation, inhibition, and cross-regulation, respectively. 2.6 Regulation of cholesterol homeostasis Cholesterol homeostasis is tightly regulated by two families of transcription factors: sterol regulatory element-binding proteins (SREBPs) ( 42 ) and liver X receptors (LXRα and β isoforms) ( 43 , 44 ). Sterol regulatory element-binding protein 2 (SREBP2) regulates cholesterol uptake by inducing the expression of the LDLR ( 2 ). In contrast, LXRs promote cholesterol efflux and facilitate its transport back to the liver via reverse cholesterol transport for excretion ( 45 ). Dysregulation of cholesterol homeostasis is a characteristic feature of cancer cells. Owing to their markedly increased proliferation rates compared with normal cells, cancer cells require higher levels of cholesterol for membrane biogenesis and signal transduction ( 46 , 47 ). Intracellular cholesterol levels are regulated by these transcription factors. Cholesterol depletion activates SREBPs, leading to upregulation of genes such as HMGCR and LDLR, thereby promoting cholesterol synthesis and uptake. Conversely, when cholesterol levels are elevated, LXRs are activated, stimulating the expression of genes involved in cholesterol efflux and excretion, including ABCA1 and ABCG1, and facilitating transport back to the liver in the form of HDL complexes ( 48 , 49 ). This establishes a finely tuned feedback regulatory circuit ( 50 ). Tumor cells exploit this regulatory system to meet the metabolic demands of malignant proliferation. In hematologic malignancies, SREBP2 is activated in AML, DLBCL, and MM, upregulating LDLR/HMGCR/SQLE to enhance cholesterol uptake/synthesis ( 42 , 51 , 52 ). In contrast, LXRs are suppressed, reducing ABCA1/ABCG1 efflux and promoting cholesterol accumulation for clonal growth ( 43 – 45 ), though LXR may induce apoptosis in MM ( 41 ). This SREBP-activated/LXR-repressed axis drives metabolic reprogramming. In T cells, SREBP supports lipid raft integrity and TCR signaling; in CLL, impaired SREBP1/2 activation downregulates LDLR expression and reduces cholesterol uptake, promoting T-cell exhaustion and compromising the efficacy of immune checkpoint inhibitors—a defect further exacerbated by hypocholesterolemia ( 53 , 54 ). In macrophages, SREBP2 drives M1 polarization, but low cholesterol favors M2-like TAMs with IL-10 ( 55 , 56 ). LXR regulates macrophages via efflux/anti-inflammation, varying by model. SREBP supports HSC self-renewal, LXRs regulate quiescence; dysregulation aids preleukemic evolution ( 47 ). This cell-type-specific regulation forms a metabolic-immune network with therapeutic potential. In sharp contrast to normal hematopoietic cells—where SREBP2 and LXRs operate in a balanced feedback loop to maintain physiological cholesterol levels—malignant cells in hematologic neoplasms reprogram this regulatory circuitry toward a “dual-assurance” strategy. This is characterized by sustained SREBP2-driven upregulation of LDLR/HMGCR/SQLE to maximize cholesterol uptake and de novo synthesis, coupled with LXR-mediated suppression of ABCA1/ABCG1 to minimize cholesterol efflux. Such a polarized metabolic adaptation not only ensures sufficient cholesterol supply for rapid membrane biosynthesis and oncogenic signaling, but also distinguishes tumor cells from their normal counterparts, providing a mechanistic basis for the hypocholesterolemia observed in patients. 3 Cholesterol levels in hematological malignancies Cholesterol is indispensable for cancer cell proliferation and performs several critical biological functions. Studies have shown that patients with lung cancer ( 57 ,
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