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Cholesterol metabolism and cancer: Molecular mechanisms, immune regulation and an epidemiological perspective (Review)

  • Authors:
    • Zeyin He
    • Lili Zhang
    • Shiyi Gong
    • Xudan Yang
    • Guixuan Xu
  • View Affiliations / Copyright

    Affiliations: Department of Pathology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China, Clinical Nutrition Section, Department of Laboratory Medicine, The Third People's Hospital of Chengdu, Chengdu, Sichuan 610014, P.R. China, Department of Nutrition and Food Hygiene, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
    Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 226
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    Published online on: October 17, 2025
       https://doi.org/10.3892/ijmm.2025.5667
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Abstract

Cholesterol and its metabolites exert multifaceted and profound effects on cancer initiation, progression and therapeutic response as well as patient prognosis. The present review systematically summarizes the oncogenic role of cholesterol metabolism in malignancies. Cancer cells extensively remodel cholesterol homeostasis through enhanced synthesis, increased uptake and impaired efflux, thereby sustaining proliferative signaling, suppressing ferroptotic cell death, promoting autophagic survival and facilitating epithelial‑mesenchymal transition, collectively fueling tumor invasion and metastasis. Within the tumor immune microenvironment, cholesterol exhibits dual immunoregulatory roles; it potentiates T‑cell antitumor function while its oxidized derivatives contribute to T‑cell exhaustion. Therapeutic targeting of cholesterol metabolism represents a promising strategy to trigger ferroptosis, reverse chemoresistance and reinvigorate antitumor immunity. Nevertheless, epidemiological evidence regarding the correlation between cholesterol levels and cancer risk remains contentious, underscoring the context‑dependent and complex nature of cholesterol in oncology. Targeting cholesterol metabolism may thus offer a novel integrative approach for cancer therapy, meriting further mechanistic and clinical investigation.
View Figures

Figure 1

Cholesterol metabolism and cancer.
The major pathways involved in intracellular cholesterol metabolism
include biosynthesis, uptake, efflux, esterification and
conversion. Intracellular cholesterol levels are precisely
regulated through these pathways and cholesterol transport. (A)
De novo biosynthesis converts acetyl-CoA to cholesterol
through ~30 enzymatic steps, with HMGCR and SQLE serving as key
rate-limiting enzymes. HMGCR, a glycoprotein localized to the ER,
reduces HMG-CoA to MVA. SQLE, another rate-limiting enzyme
downstream of HMGCR in cholesterol biosynthesis, converts the
non-sterol intermediate squalene into 2,3-oxysqualene. (B) Besides
synthesis, cells acquire cholesterol via LDLR-mediated endocytosis
of LDL particles. LDL-derived cholesterol is transported via
endosomes and lysosomes, with the assistance of NPC1/2 and sterol
transfer proteins, to the plasma membrane and ER. Cholesterol can
be converted into CE by ACAT1 and stored in lipid droplets; it can
also be transformed into hydroxycholesterol, epoxycholesterol,
vitamin D and steroid hormones. Excess cholesterol in the cell is
secreted extracellularly via ABCA1/ABCG1. HMG-CoA,
3-hydroxy-3-methylglutaryl-CoA; HMGCS, HMG-CoA synthase; HMGCR,
3-hydroxy-3-methylglutaryl-CoA reductase; SQLE, squalene epoxidase;
MVA, mevalonate; IPP, isoprene unit isopentenyl diphosphate; FDPS,
farnesyl diphosphate synthase; FPP, farnesyl pyrophosphate; FDFT1,
farnesyl-diphosphate farnesyltransferase 1; LSS, lanosterol
synthase; LDL, low-density lipoprotein; LDLR, LDL receptor; SCAP,
sterol regulatory element binding protein cleavage-activating
protein; SR-B2, scavenger receptor class B protein; CE, cholesterol
ester; EE, early late endosome; LE, late endosome; Ly, lysosome;
ER, endoplasmic reticulum; ACAT1/2, acetyl-CoA acetyltransferase
1/2; NPC1/2, Niemann-Pick C1-like protein 1/2; ABCA1, ATP binding
cassette transporter A1; ABCG1, ATP-binding cassette transporter
G1.

Figure 2

Genes and cholesterol metabolism.
Schematic representation of the mechanism by which genes regulate
cholesterol biosynthesis, uptake, efflux and esterification. PTEN,
mutations in the phosphatase and tensin homolog; PI3K,
phosphatidylinositol 3-kinase; SREBP, sterol regulatory binding
protein; mTOR, mechanistic target of rapamycin; MVA, mevalonate;
PCSK9, proprotein convertase subtilisin kexin/type 9; ATF3,
activating transcription factor 3; ERK,
extracellular-signal-regulated kinase; LDLR, low-density
lipoprotein receptor; LXR, liver X receptor; ABCA1, ATP binding
cassette transporter A1; ABCG1, ATP-binding cassette transporter
G1; CE, cholesterol ester; ACAT1, acetyl-CoA acetyltransferase
1.

Figure 3

Regulation of ferroptosis by the
cholesterol biosynthesis pathway. 7-DHC, 27-HC and B-ring sterols
activate the ferroptosis process by upregulating GPX4, FSP1, PTGS2,
FT1 and FTH expression. Inhibition of key enzymes of cholesterol
metabolism such as HMGCR and IPP are expected as promising
approaches to induce ferroptosis in cancer cells. HMGCR,
3-hydroxy-3-methylglutaryl-CoA reductase; HDL, high-density
lipoprotein; 27-HC, 27-hydroxycholesterol; GPX4, glutathione
peroxidase 4; SIM, simvastatin; RSL3, ras-selective lethal 3; IPP,
isoprene unit isopentenyl diphosphate; Fe-MOF/CP, iron
metal-organic framework/cholesterol oxidase and PEGylation; FSP1,
Ferroptosis suppressor protein 1; PD-L1, programmed death ligand 1;
SREBP2, sterol regulatory binding protein 2; 7-DHC,
7-dehydrocholesterol.

Figure 4

Cholesterol-induced activation of
autophagy. Exogenous cholesterol supplementation and elevated
endogenous cholesterol activate mTORC1-dependent autophagy through
multiple pathways, including those involving p53, AKT and NPC1.
Additionally, cholesterol derivatives such as 25-HC and 5,6-EC also
stimulate autophagy in tumor cells. CEMM, cholesterol-enriched
membrane micro-domains; 25-HC, 25-hydroxycholesterol; RBP-JK,
DNA-binding protein recombination signal binding protein-Jκ; VAMP3,
vesicle-associated membrane protein; GOLM1, Golgi membrane protein
1; RTK, receptor tyrosine kinase; PI3K, phosphatidylinositol
3-kinase; SREBP, sterol regulatory binding protein; mTOR,
mechanistic target of rapamycin; SNHG6, small nucleolar RNA host
gene 6; FAF2, Fas-associated factor family member 2; SLC38A9,
solute carrier family 38 member 9; NPC1, Niemann-Pick C1.

Figure 5

Cholesterol promotes EMT progression.
High cholesterol levels facilitate EMT by activating signaling
pathways including TGF-β/MAPK, Wnt/β-catenin, PI3K/AKT/mTOR,
PARP1/COL5A1/FAK and APMAP/EPS15R/EGFR. Conversely, LXR-induced
upregulation of ABCA1 and ABCG1 suppresses EMT in tumor cells. EMT,
epithelial-mesenchymal transition; TGF-β, transforming growth
factor β; MAPK, mitogen-activated protein kinase; PI3K,
phosphatidylinositol 3-kinase; mTOR, mechanistic target of
rapamycin; PARP1, Poly (ADP-ribose) polymerase 1; COL5A1, collagen
type V α1 chain; FAK, focal adhesion kinase; APMAP, adipocyte
plasma membrane associated protein; EGFR, epidermal growth factor
receptor; EPS15R, EGFR-substrate 15-related protein; LXR, liver X
receptor; ABCA1, ATP binding cassette transporter A1; ABCG1,
ATP-binding cassette transporter G1; HCD, high cholesterol diet;
SOAT1, sterol O-acyltransferases 1; ERK1/2, extracellular
signal-related kinases 1 and 2.

Figure 6

Impact of cholesterol and derivatives
on the adaptive immune system. Cholesterol regulates T cell
function through direct binding to the TCR or through indirect
mechanisms, influencing immune synapse formation. Excessive
cholesterol impairs T cell activity; it also promotes M2 macrophage
polarization via the STAT3/NF-κB/PD-L1 axis. The oxysterol 27-HC
induces T cell apoptosis through SREBP inhibition and LXR
activation. Genes involved in cholesterol transport and metabolism
(such as ACAT1/2, LCAT, CETP, CYP11A1, CYP17A1 and CYP7A1) modulate
cholesterol levels in γδ T cells. Cholesterol enhances IL-9
secretion in macrophages but inhibits CCR7 in DCs; it also promotes
Th17 cell differentiation and suppresses IFN-γ production in
macrophages. TCR, T-cell receptor; STAT3, signal transducer and
activator of transcription 3; NF-κB, nuclear factor κB; PD-L1,
programmed death-1; 27-HC, 27-hydroxycholesterol; SREBP, sterol
regulatory binding protein; LXR, liver X receptor; ACAT1/2,
acetyl-CoA acetyltransferase 1/2; LCAT, lecithin cholesterol
acyltransferase; CETP, cholesteryl ester transfer protein; CYP11A1,
enzyme cytochrome P450 family 11 subfamily A member 1; CYP17A1,
enzyme cytochrome P450 family 17 subfamily A member 1; CYP7A1,
cholesterol 7α-hydroxylase; IL-9, interleukin-9; CCR7, chemokine
receptor 7; DCs, dendritic cells; IFN-γ, interferon-γ; Th17,
intestinal IL-17-producing T helper; 7-DHC,
7-dehydrocholesterol.
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Spandidos Publications style
He Z, Zhang L, Gong S, Yang X and Xu G: Cholesterol metabolism and cancer: Molecular mechanisms, immune regulation and an epidemiological perspective (Review). Int J Mol Med 56: 226, 2025.
APA
He, Z., Zhang, L., Gong, S., Yang, X., & Xu, G. (2025). Cholesterol metabolism and cancer: Molecular mechanisms, immune regulation and an epidemiological perspective (Review). International Journal of Molecular Medicine, 56, 226. https://doi.org/10.3892/ijmm.2025.5667
MLA
He, Z., Zhang, L., Gong, S., Yang, X., Xu, G."Cholesterol metabolism and cancer: Molecular mechanisms, immune regulation and an epidemiological perspective (Review)". International Journal of Molecular Medicine 56.6 (2025): 226.
Chicago
He, Z., Zhang, L., Gong, S., Yang, X., Xu, G."Cholesterol metabolism and cancer: Molecular mechanisms, immune regulation and an epidemiological perspective (Review)". International Journal of Molecular Medicine 56, no. 6 (2025): 226. https://doi.org/10.3892/ijmm.2025.5667
Copy and paste a formatted citation
x
Spandidos Publications style
He Z, Zhang L, Gong S, Yang X and Xu G: Cholesterol metabolism and cancer: Molecular mechanisms, immune regulation and an epidemiological perspective (Review). Int J Mol Med 56: 226, 2025.
APA
He, Z., Zhang, L., Gong, S., Yang, X., & Xu, G. (2025). Cholesterol metabolism and cancer: Molecular mechanisms, immune regulation and an epidemiological perspective (Review). International Journal of Molecular Medicine, 56, 226. https://doi.org/10.3892/ijmm.2025.5667
MLA
He, Z., Zhang, L., Gong, S., Yang, X., Xu, G."Cholesterol metabolism and cancer: Molecular mechanisms, immune regulation and an epidemiological perspective (Review)". International Journal of Molecular Medicine 56.6 (2025): 226.
Chicago
He, Z., Zhang, L., Gong, S., Yang, X., Xu, G."Cholesterol metabolism and cancer: Molecular mechanisms, immune regulation and an epidemiological perspective (Review)". International Journal of Molecular Medicine 56, no. 6 (2025): 226. https://doi.org/10.3892/ijmm.2025.5667
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