Cholesterol is an essential component of mammalian
cell membranes and is indispensable for maintaining normal cellular
functions (1). The synthesis of
cholesterol is maintained through a dynamic homeostatic process,
with intracellular cholesterol levels being precisely regulated by
a sophisticated feedback system involving synthesis, uptake,
efflux, transport, esterification and enzymatic conversion
(2). Cancer cells frequently
exhibit an elevated demand for cholesterol to facilitate their
growth (3). Specifically, they
augment the uptake of exogenous cholesterol and lipoproteins and
reprogram cholesterol metabolism by regulating genes related to
cholesterol synthesis, efflux and intake to increase cholesterol
influx and decrease efflux (4,5).
Additionally, tumors can elevate cholesterol levels within the
tumor microenvironment (TME) by stimulating cholesterol efflux from
monocytes and macrophages via intercellular signaling (6). Furthermore, cholesterol serves as a
precursor for biologically active metabolites, such as oxysterols
(7), steroid hormones (8) and lipid rafts (LRs) (9), which collectively promote cancer
cell proliferation, angiogenesis, metastasis and other
pro-tumorigenic processes (10).
A previous study has shown that the crosstalk
between cholesterol metabolism and the TME contributes to
tumorigenesis and progression (11). Moreover, oncogenic signaling
pathways (12), ferroptosis
(13), autophagy (14), epithelial-mesenchymal transition
(EMT) (15) and the immune
response (16) are modulated
through cholesterol metabolism. Current evidence indicates that
targeting cholesterol metabolism, either alone or in combination
with other strategies, to enhance cancer treatment efficacy has
proven to be a viable antitumor approach. Notably, interventions
targeting cholesterol metabolism enzymes [such as HMG-CoA reductase
(HMGCR) (17), sterol regulatory
element binding proteins (SREBPs) (18), squalene epoxidase (SQLE)
(19) and acetyl-CoA
acetyltransferase 1 (ACAT1) (20)] or transporters [ATP-binding
cassette transporter A1 (ABCA1) (21), ATP-binding cassette transporter
G1 (ABCG1) (22) and low-density
lipoprotein receptor (LDLR) (23)] have shown considerable anticancer
potential.
However, the association between cholesterol and
cancer progression is currently controversial. Several
epidemiological studies have shown that hypercholesterolemia and
high cholesterol diets are associated with an increased risk of
developing hepatocellular carcinoma (HCC) (24), colorectal cancer (CRC) (25), prostate cancer (PC) (26) and other cancer types (27). Consistently, statins and
proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors,
which effectively lower serum cholesterol levels by targeting
cholesterol metabolism genes, have been found to suppress cancer
progression in certain settings (28). By contrast, other large cohort
studies report that serum total cholesterol (TC) levels are either
inversely correlated with cancer risk or show no significant
association (29,30). For instance, a large-scale
prospective Korean cohort study demonstrated that higher TC levels
were negatively associated with mortality rates in HCC and gastric
cancer (GC) (31). The role of
dietary cholesterol in carcinogenesis is similarly debated. While
high-cholesterol diets have been shown to accelerate HCC and CRC
development (32), a recent
study showed a significant positive association between higher
daily dietary cholesterol intake and ovarian cancer (OV) risk,
whereas abnormal lipid levels were not associated with the risk of
OV (33). These conflicting
epidemiological data underscore the complexity of the role of
cholesterol in cancer and highlight the need for further
mechanistic and population-level studies to clarify the
relationship between serum cholesterol levels and cancer risk.
In the present review, the latest progress in the
interaction between cholesterol and cancer progression is
summarized, focusing on the functional roles of cholesterol and its
derivatives within cancer cells and their reciprocal regulation
within the TME. The current therapeutic strategies targeting
molecules such as HMGCR, SREBPs and SQLE are also discussed,
offering new perspectives for anticancer drug development.
Cholesterol is an essential lipid molecule and a
critical component for maintaining normal functions in the human
body (1,34). Cholesterol fulfills multiple
vital roles, including maintaining membrane integrity, facilitating
cell signaling cell membrane structure, mediating cell
communication, enhancing immunity and serving as a precursor for
synthesizing steroids, sex hormones, vitamin D, bile salts and
oxysterols (35-37). Cholesterol metabolites also hold
significant value. In the liver, cholesterol is converted into bile
acids, which are essential for the emulsification and absorption of
dietary lipids and represent the primary route for eliminating
excess cholesterol from the body (38,39). Moreover, cholesterol serves as
the precursor for all steroid hormones (such as cortisol,
aldosterone, estrogen and testosterone). In the skin, under
ultraviolet radiation, cholesterol is transformed into a vitamin D
precursor, which is subsequently activated to regulate calcium and
phosphate homeostasis (40-42). Thus, in healthy individuals, the
homeostasis of cholesterol metabolism is indispensable for cellular
activity, digestion function, endocrine regulation and skeletal
health.
The body acquires cholesterol through two primary
pathways: Endogenous synthesis (70-80%) and exogenous dietary
intake (20-30%) (43). Dietary
cholesterol is absorbed by Niemann-Pick-C1 like-1 protein (NPC1L1)
on the intestinal epithelial cell membrane and subsequently
esterified by ACAT1/2, enabling its uptake by the liver in the form
of chylomicrons (44). The liver
esterifies cholesterol synthesized internally and absorbed from
food, assembling it with apolipoproteins and other components into
very low-density lipoproteins (VLDLs), which are subsequently
secreted into the bloodstream. These VLDLs are metabolized into
low-density lipoproteins (LDLs), which are taken up by peripheral
tissues via LDLRs. Excess cholesterol in peripheral tissues is
delivered back to the liver via high-density lipoprotein
cholesterol (HDL-C)-mediated reverse cholesterol transport, where
it can be recycled or converted to bile acids for excretion
(1,45). Intracellular cholesterol levels
are regulated through receptor-mediated endocytosis of LDL-C and
HDL-C, as well as through de novo synthesis in the
endoplasmic reticulum (ER) via the mevalonate (MVA) pathway, which
includes squalene biosynthesis and modification procedures
(34). Key regulatory enzymes in
this pathway are HMGCR and SQLE, which catalyze the conversion of
HMG-CoA to MVA and squalene to 2,3-epoxysqualene, respectively.
Subsequent steps involve enzymes such as farnesyl diphosphate
synthase (FDPS) and geranylgeranyl pyrophosphate synthase (GGPPs),
which are crucial for the biosynthesis of farnesyl pyrophosphate
(FPP) and geranylgeranyl pyrophosphate (GGPP). Under the action of
squalene synthase and squalene epoxidase, FPP is converted to
squalene and eventually to cholesterol (46).
Cholesterol homeostasis is transcriptionally
regulated by SREBPs. When intracellular cholesterol levels are
high, SREBPs are retained in the ER through interaction with the
SREBP cleavage-activating protein/insulin-induced gene-1 (INSIG-1)
complex. When the cholesterol level of the endoplasmic membrane
decreases, SREBPs are transported to the Golgi apparatus. Following
proteolytic processing, their transcriptionally active N-terminal
domains are released (47).
Excess intracellular cholesterol is either esterified by ACAT1 and
stored in lipid droplets or refluxed from cells via transporters
such as ABCA1 and ABCG1 (48).
The dysregulation of cholesterol metabolic enzymes is implicated in
various pathologies, including familial hypercholesterolemia
(49), atherosclerosis (35) and Alzheimer's disease (50). In summary, cholesterol levels in
normal cells are tightly controlled through a balance of synthesis,
uptake, efflux, transport and esterification. A thorough
understanding of these regulatory mechanisms is essential for
elucidating the pathophysiology of cholesterol-related disorders
(Fig. 1).
During growth and invasion, cancer cells require a
continuous supply of cholesterol to sustain biosynthetic processes
and cellular functions. Consequently, abnormal activation of
cholesterol metabolism genes is commonly observed across multiple
types of cancer (51).
Cholesterol metabolism-related genes are upregulated, cholesterol
influx is increased and cholesterol efflux is decreased. HMGCR is
the primary rate-limiting enzyme in cholesterol biosynthesis, and
its high expression in malignant tumors promotes tumor progression.
For instance, HMGCR induces immunosuppression in OV by activating
X-box binding protein 1 and programmed death-ligand 1 (PD-L1),
correlating with poor prognosis (52). In PC, stromal HMGCR upregulation
induced by coculture with malignant cells promotes tumor growth
(53). HCC is an aggressive
human cancer with increasing incidence worldwide (54). Research has revealed that HMGCR
promotes tumor growth in a mouse model of primary liver cancer by
enhancing cholesterol synthesis and activating the PDZ-binding
motif/TEA domain transcription factors 2/anillin/kinesin family
member 23 pathway (55).
Additionally, HMGCR overexpression augments the growth and
migration of GC cells (56),
breast cancer (BC) cells (57)
and glioblastoma (GBM) cells (58).
SQLE, as the second rate-limiting enzyme downstream
of HMGCR, is considered an oncogene that promotes carcinogenic
signaling (68). It has been
reported that SQLE could enhance the PI3K/AKT signaling pathway to
promote distant metastasis in head and neck squamous cell carcinoma
(69). In CRC, SQLE induces EMT
by triggering the Wnt/β-catenin pathway, thereby promoting tumor
metastasis (70). Moreover,
SQLE, which is abnormally expressed in liver cancer models, induces
immune suppression by promoting cholesterol accumulation in the TME
and inhibiting CD8+ T cell function (71). Research has also shown that SQLE
contributes to the resistance of BC cells to apoptosis by enhancing
glycolysis (72). SQLE
expression is specifically elevated in HCC and is strongly
associated with poor clinical outcomes (73). SQLE significantly augments HCC
growth in both in vitro and in vivo models, linked to
the activation of serine-threonine kinase receptor associated
protein-dependent transforming growth factor-β (TGF-β)/SMAD
signaling pathways (74).
Farnesyl-diphosphate farnesyltransferase (FDFT1),
another key enzyme in the cholesterol pathway, is dysregulated in
various tumor types and represents a potential biomarker and
therapeutic target (75). FDFT1
is highly expressed in HCC tissues and is correlated with poor
patient prognosis (76,77). In HCC, FDFT1 suppressed
fructose-1,6-bisphosphate aldolase B expression, thereby releasing
its inhibitory control over the AKT signaling pathway and
activating the PI3K/AKT pathway, ultimately promoting tumor growth
and metastasis (76). Prognosis
analysis showed that FDFT1, as a potential prognostic marker, was
associated with shorter survival in patients with CRC and may
partially contribute to the formation of a suppressive immune
microenvironment (78). This
indicates that the tumor-promoting effect of FDFT1 is dependent on
the TME (79). Notably, another
study has revealed a unique role of FDFT1 in CRC. This study found
that under fasting conditions, SREBP2 upregulates FDFT1 expression,
while elevated FDFT1 expression negatively regulates the
AKT/mTOR/hypoxia-inducible factor-1α (HIF-1α) signaling pathway,
thereby inhibiting glycolysis and proliferation in CRC cells
(80). This suggests that FDFT1
may exert tumor-suppressive effects under specific metabolic
conditions, such as fasting, indicating the complexity of its
functional role.
ACAT1 is a multifunctional metabolic enzyme that
plays a complex and sometimes seemingly contradictory role in
various cancer types; it can suppress tumors under specific
conditions while simultaneously promoting tumor progression through
different mechanisms (81). In
HCC, ACAT1-mediated acetylation of glycerophosphate
O-acyltransferase (GNPAT) can stabilize GNPAT protein levels
by antagonizing tripartite motif containing 21-catalyzed
ubiquitination, ultimately promoting xenograft tumor growth
(82). In bladder cancer (BLCA),
ACAT1 promotes BLCA cell proliferation and invasion by activating
the AKT/GSK3β/c-Myc signaling pathway (83). Additionally, a recent study has
identified ACAT1 as a key factor in reducing the sensitivity of GBM
to ferroptosis, with its mechanism of action dependent on the
regulation of the iron efflux protein, solute carrier family 40
member 1 (84). However, under
the influence of exogenous proinflammatory factors interleukin
(IL)-12 and IL-18 proteins, ACAT1 is phosphorylated at the S60 site
and translocates from mitochondria to the nucleus. Within the
nucleus, it exerts its acetyltransferase activity, specifically
acetylated the K146 site of the NF-κB family protein p50, thereby
releasing its transcriptional repression on multiple immunochemical
genes and natural killer (NK) cell activation ligands, thereby
powerfully recruiting and activating NK cells. This enhances their
tumor-killing capacity and inhibits tumor growth (85).
NPC1L1 is the primary protein responsible for the
absorption of exogenous cholesterol. NPC1L1 is highly expressed in
CRC and serves as an independent prognostic factor that is
significantly correlated with pathological staging (86,87). An in vitro study revealed
that targeting NPC1L1 with ezetimibe blocks the AKT/mTOR signaling
pathway in HCC and suppresses cancer cell activity (88).
Collectively, these findings underscore that
cholesterol metabolism is notably reprogrammed in cancer cells,
with multiple enzymes in the biosynthetic pathway actively
contributing to tumor development and progression.
Numerous studies have demonstrated that aberrantly
activated genes or signaling pathways can promote cancer cell
proliferation and suppress apoptosis through the regulation of
cholesterol metabolism-related genes (89-93). For instance, the tumor suppressor
p53 can inhibit the MVA pathway, and its deficiency or mutation
releases multiple constraints on tumor growth (94). The p53 protein directly
suppresses the transcription of SQLE and SREBP genes by binding to
their promoters, thereby downregulating the MVA pathway in CRC,
HCC, OV and BC (95). By
contrast, upregulated or unmutated p53 transcriptionally induces
ABCA1 gene expression to block SREBP2 activation and inhibit the
MVA pathway (96,97). In recent years, the function of
the tumor suppressor phosphatase and tensin homolog protein (PTEN)
in metabolic regulation has attracted significant attention
(98). As a phosphatase, PTEN
dephosphorylates phosphatidylinositol-3,4,5-trisphosphate, thereby
directly inhibiting the oncogenic PI3K/AKT/mTOR signaling pathway
(99). PTEN suppression in
endocrine therapy-resistant BC cells leads to increased SQLE
expression and a corresponding sensitization to the inhibition of
cholesterol synthesis (100).
In pancreatic ductal adenocarcinoma (PDAC), PTEN deficiency
enhances the protein stability of SQLE by activating the
PI3K/AKT/GSK3β-mediated proteasome pathway (101). Activated AKT phosphorylates the
cytoplasmic phosphorylating rate-limiting enzyme
phosphoenolpyruvate carboxy kinase 1, which is translocated to the
ER and acts as a protein kinase that phosphorylates the INSIG
protein and disrupts the interaction between the INSIG protein and
the SREBP shear-activating proteins, which in turn activates the
transcription of SREBPs as well as downstream genes related to
lipid synthesis and uptake and promotes the progression of HCC
(102). AKT regulates SREBP
activation by activating mTOR1; it promotes the protein expression
of nuclear SREBP2 through a dual mechanism: First, by
phosphorylating and inhibiting its nuclear translocation inhibitor,
lipin1; second, by regulating cholesterol transport from lysosomes
to the ER (103). Furthermore,
suppression of ciliary function activates the Wnt/β-catenin
pathway, which synergistically promotes transcription of MVA
pathway genes by directly interacting with SREBP2 (104).
Liver X receptors (LXRs) are nuclear receptors and
members of the nuclear receptor family that regulate intracellular
lipid homeostasis. Activated by high intracellular cholesterol,
LXRs function as cholesterol sensors (105). c-Fos promotes alterations in
cholesterol metabolism by suppressing the transcriptional activity
of LXRα, leading to the accumulation of toxic sterols and bile
acids, thereby promoting hepatocellular carcinogenesis (106). High expression of anoctamin-1
contributes to in vivo metastasis of primary esophageal
squamous cell carcinoma by inhibiting LXR signaling, leading to
cholesterol accumulation and decreased cholesterol hydroxylation
via downregulation of the expression of the cholesterol hydroxylase
cytochrome P450 family 27 subfamily A member 1 (107).
LDLR is the key molecule that maintains cholesterol
balance in the body, releasing cholesterol into cells for
utilization while simultaneously lowering cholesterol levels in the
blood (108). LDLR-mediated
cholesterol uptake plays a contributory role in cancer (109). A recent study has demonstrated
that leukocyte immunoglobulin-like receptor B1 directly binds to
the LDLR protein to form a complex, thereby enhancing LDLR-mediated
cholesterol uptake and conferring resistance to ferroptosis in
multiple myeloma (MM) cells (110).
Apolipoprotein B (APOB) is an essential structural
component of VLDL and LDL; its C-terminal region contains an
LDLR-binding domain that specifically recognizes LDLRs on
hepatocyte surfaces, mediating LDL uptake and clearance to maintain
plasma cholesterol homeostasis (111). APOB is classified into two
primary subtypes: i) ApoB-100, which is synthesized in the liver
and serves as the major structural protein of VLDL,
intermediate-density lipoprotein (IDL), and LDL; and ii) ApoB-48,
which is synthesized in the small intestine, constitutes the core
component of chylomicrons and is primarily responsible for
transporting dietary lipids (112). APOB is closely associated with
metastasis in CRC and liver cancer. Compared with the control
group, silencing of APOB in HCC cells has been shown to increase
the relative rate of cell proliferation (113). A recent nested case-control
study revealed that genetically predicted APOB levels are
associated with a 31% reduction in HCC risk [95% confidence
interval (CI), 19-42%] and each 0.1 g/l increase in circulating
APOB levels was linked to an 11% decrease in HCC risk (95% CI,
8-14%) (114). Another
prospective cohort study from Sweden also found that elevated
circulating levels of APOB increased the risk of developing CRC
(115).
PCSK9 is a key regulator of LDLR protein levels,
binding to LDLRs on the cell surface and directing them to
lysosomes for degradation (116). In the TME, tumor cell-derived
PCSK9 disrupts T-cell receptor signaling by binding to LDLR on the
membrane of CD8+ T cells and directing LDLR to lysosomal
degradation. This impaired CD8+ T cell activation,
proliferation and effector function, ultimately leads to lymphoma
metastasis in mice (117). In
lung adenocarcinoma (LUAD), the long non-coding RNA EMX2OS
competitively binds to microRNA-1185-5p to regulate the LDLR,
thereby promoting lung cancer cell proliferation and invasion
(118). In addition, MEK/ERK
signaling increases intracellular cholesterol uptake by
upregulating LDLR expression, leading to HCC metastasis (119).
Similarly, dysregulation of cholesterol metabolism
can activate gene expression. Poly (ADP-ribose) polymerase 1
(PARP1) is a multifunctional human ADP-ribosyl transferase
(120). In addition to
maintaining genomic integrity, PARP1 participates in
transcriptional regulation (121). A recent study revealed that
long-term high cholesterol promotes OV progression by activating
focal adhesion kinase (FAK)/collagen type V alpha 1 chain (COL5A1)
signaling through the upregulation of PARP1 expression (122). Several cholesterol derivatives
and metabolites, including 7-ketocholesterol (123), 15α-hydroxycholesterol (124), 25-hydroxycholesterol (25-HC)
(125), 17-β-estradiol
(126) and vitamin D (127), have been shown to induce PARP1
expression.
Cholesterol is a key structural component of LRs. In
PC cells, elevated serum cholesterol levels can increase
cholesterol content within tumor cell liposomes, thereby activating
the LR-mediated Src/PI3K/AKT signaling pathway (128,129). Mitochondrial cholesterol also
exhibits physiological activity and promotes tumor cell
proliferation and metastasis. For instance, a recent study revealed
that the interaction between cytotoxin-associated protein A and
cytochrome P450scc (CYP11A1) promotes mitochondrial cholesterol
accumulation. This accumulated cholesterol then activates
autophagy, thereby enhancing GC cell proliferation and suppressing
apoptosis (130). The c-Myc
proto-oncogene encodes a family of transcription factors and is one
of the most commonly activated oncogenes in human tumors (131). Yang et al (132) found that c-Myc protein directly
promotes SQLE transcription, thereby increasing cholesterol
production and promoting tumor cell growth. Similarly, activated
c-Myc protein has also been observed to enhance HMGCR
transcriptional expression in T-cell acute lymphoblastic leukemia
(133). Notably, upregulated
SREBP1 protein directly interacts with SREBP1 binding elements in
the c-Myc promoter region in PC to induce c-Myc activation to drive
tumor stemness and metastasis (134). These studies illustrate a
reciprocal regulatory relationship between cholesterol metabolism
and genes, highlighting their critical roles in tumor cell
proliferation and invasion (Fig.
2).
A large body of preclinical evidence has underscored
the critical and multifaceted roles of cholesterol metabolism in
cancer progression (135-138). Targeting key nodes of this
pathway, such as inhibition of the MVA pathway, has emerged as a
promising antitumor strategy (1,139). At present, statins, which act
as inhibitors of HMGCR, and PCSK9 inhibitors have emerged as the
predominant agents targeting cholesterol metabolism, extensively
employed in both basic and clinical research (140,141). The anticancer function of
statins has attracted significant attention. Existing evidence
indicates that statins can promote tumor cell proliferation,
differentiation and apoptosis (76,142,143). A clinical study demonstrated
that initiating statin therapy within 1 year of diagnosis results
in a 58% relative improvement in BC-specific survival and a 30%
relative improvement in OS (144). Similarly, simvastatin (SIM)
blocks the isoprenylation of Rab5 GTPase and its mediated endosomal
maturation in antigen-presenting cells by depleting GGPP through
inhibition of the MVA pathway, ultimately enhancing antitumor
immunity by boosting antigen presentation and T cell activation
(145). Bisphosphonates (BPs)
are another widely studied inhibitor of the MVA pathway, which
inhibits FDPS activity and prevents the conversion of isopentenyl
pyrophosphate (IPP) to FPP (47,146,147). Bisphosphonate therapy has been
reported to improve the prognosis of patients with bona fide MM, PC
and BC (148). Moreover, BPs
can reduce bone and visceral metastases in women with BC (149,150). Previous studies suggest that
SQLE upregulation is closely associated with tumor progression. For
instance, upregulated SQLE promotes HCC cell invasion by activating
ERK (151) or AKT/mTOR
signaling (152). However,
targeting SQLE with terbinafine can delay tumor progression in
endometrial cancer (ECa) (153), PC (154), CRC (155), HCC (156) and BC (157). Ezetimibe is an FDA-approved
drug that acts on NPC1L1 to inhibit the progression of CRC
(86), BC (158) and PC (159) by inhibiting intestinal
cholesterol absorption. Intracellular cholesterol accumulation
triggers LXRs and excess cholesterol is excreted via ABCA1 or ABCG1
(160). The LXR agonists
RGX-104 (161), LXR 623
(162) and T0901317 (163) increase ABCA1 expression in a
variety of tumor cells, decrease intracellular cholesterol levels
and effectively inhibit the growth of mouse xenograft tumors.
Additionally, T0901317 can reduce myeloid-derived suppressor cell
infiltration through the LXR/APOE pathway, thereby lifting immune
suppression, enhancing T cell function and ultimately improving
overall immune therapy response (164).
The NPC1 protein, which regulates endolysosomal
cholesterol transport, has recently emerged as a therapeutic
target. NPC1 represents a convergence point for cholesterol derived
from LDL, HDL and VLDL, allowing simultaneous targeting of multiple
cholesterol sources (170). A
previous study has shown that targeted inhibition of NPC1
downregulates mTORC1 signaling and reduces autophagy and tumor
growth (171). Moreover,
lowering NPC1 expression enhances the therapeutic efficacy of
cisplatin or trastuzumab in NSCLC (172), GC (173) and PC (174), leading to improved patient
prognosis. These findings highlight the clinical potential of
combining cholesterol metabolism inhibitors with existing
anticancer agents to overcome therapy resistance. Cancer therapies
targeting cholesterol metabolism are summarized in Table I.
Ferroptosis, a regulated form of cell death driven
by iron-dependent lipid peroxidation, represents a promising
therapeutic avenue in oncology due to its involvement in tumor
progression and treatment resistance (175). Glutathione peroxidase 4 (GPX4)
and solute carrier family 7 member 11 are central to regulating
ferroptosis (176). Elevated
cholesterol levels in cancer cells have been shown to suppress
ferroptosis and impair immune responses (177). Recent studies have shown that
7-dehydrocholesterol (7-DHC) and B-ring sterols act as
free-radical-trapping antioxidants to protect mitochondrial
membranes from phospholipid autoxidation, thereby resisting
ferroptosis (178,179). While most cancer cells succumb
under stress, surviving populations often accumulate high
cholesterol levels to evade ferroptosis death (84,180,181). Chronic exposure to
27-hydroxycholesterol (27-HC), an abundant metabolite of
circulating cholesterol, causes sustained expression of GPX4 and
significantly increases the tumorigenic and metastatic capacity of
BC cells (13). These findings
highlight that aberrant cholesterol metabolism can influence cancer
pathogenesis by activating ferroptosis. In cancer cells, increased
uptake via the upregulation of lipoprotein receptors and increased
synthesis rates through the hyperactive MVA pathway results in
cholesterol accumulation, fostering cellular proliferation, tumor
metastasis and immune suppression (182-184). Studies have revealed that GPX4
relies on the output of the MVA pathway to hinder lipid
peroxidation production and ferroptosis sensitivity in HCC cells
(185,186). Exogenous cholesterol
supplementation activates the B7H3-mediated AKT/SREBP2 signaling
pathway to promote ferroptosis resistance in CRC cells as well as
xenograft tumor formation in mice (187).
Elevated cholesterol levels reduce membrane fluidity
and promote LR formation, thereby inhibiting the diffusion of lipid
peroxidation substrates and suppressing ferroptosis (188-190). A novel nanozyme composed of an
iron metal-organic framework (Fe-MOF) and nanoparticles loaded with
cholesterol oxidase and PEGylation (CP) for integrated ferroptosis
and immunotherapy, depletes cholesterol and disrupts LR integrity,
downregulates GPX4 and ferroptosis suppressor protein 1 (FSP1) and
further promotes ferroptosis. Concurrently, Fe-MOF/CP augments
immunogenic cell death, reduces programmed death-ligand 1
expression and revitalizes exhausted CD8+ T cells
(191). Similarly, in
cholesterol-addicted lymphoma cells, targeting SCARB1 via HDL
nanoparticles to reduce cholesterol uptake not only eliminates GPX4
expression but also triggers a compensatory response that enhances
cholesterol biosynthesis, ultimately leading to ferroptosis
(189). GPX4, a core regulator
of ferroptosis, is modulated by IPP, a product of the MVA pathway
and an intermediate in cholesterol synthesis. Thus, regulating the
upstream synthesis pathways of IPP using inhibitors (such as FIN56,
RSL3, statins, ML162 and ML210) induces ferroptosis by suppressing
GPX4 (a protein responsible for preventing lipid peroxide
formation); whereas FIN56 and withaferin can trigger GPX4
degradation (192). Squalene
and HMGCR are thought to exert anti-ferroptosis effects on cancer
cells (180,193). For example, SIM can inhibit the
expression of HMGCR to downregulate the MVA pathway, GPX4 and FSP1,
thereby inducing triple-negative BC cell ferroptosis (194,195). Conversely, SQLE exerts
anti-ferroptosis effects, whereas exogenous cholesterol
hydroperoxide induces dose-dependent cell death (196,197). These findings highlight the
therapeutic potential of targeting cholesterol biosynthesis to
sensitize cancer cells to ferroptosis (Fig. 3).
In cancer, autophagy exhibits a context-dependent
dual role, capable of both suppressing and promoting tumorigenesis
(198). During the early
stages, autophagy prevents tumor initiation by eliminating
oncogenic proteins, toxic misfolded aggregates and damaged
organelles (199). However, in
the later stages of tumorigenesis, autophagy functions as a dynamic
degradation and recycling system that can enhance cancer
invasiveness by promoting metastasis, thereby sustaining tumor
survival and growth (200).
Autophagy involves a variety of signaling pathways, such as the
mitogen-activated protein kinase (MAPK), mTOR, AKT, HIF-1α and p53
pathways (201). Lysosomal
cholesterol activates mTORC1 through the SLC38A9/NPC1 signaling
axis, inducing autophagy that promotes tumor metastasis and
invasion (202). Similarly,
another study revealed that cholesterol also induces autophagy in
HCC cells by activating mTORC1 via the SNHG6/FAF2/mTOR axis,
increasing the incidence of HCC driven by a high cholesterol diet
(203). In MM, researchers have
reported that cholesterol accumulation mediates autophagy
activation via the PI3K/AKT pathway (204). Conversely, phosphorylated AKT
levels as well as rapamycin signaling are markedly suppressed after
the use of statins by lowering intracellular cholesterol levels
(205). The mTOR, AKT and p53
pathways also modulate SREBP activity, which in turn regulates
cholesterol synthesis (96,206). Among these, the AKT and mTOR
pathways are the most frequently studied de novo cholesterol
synthesis pathways in cancer cells (207). mTOR serves as the core molecule
mediating the regulatory function of AKT over SREBPs. mTOR operates
through a dual mechanism: on the one hand, it is activated by AKT
(206); on the other, it drives
cholesterol biosynthesis by enhancing SREBP2 activity and
inhibiting its degradation (208). Whether cholesterol-induced
autophagy initiates positive feedback regulation of these pathways
warrants further investigation.
Emerging evidence indicates that cholesterol
enrichment within organelles facilitates the recruitment of
autophagy-initiation proteins and enhances autophagosome formation,
contributing to chemoresistance (209,210). The cholesterol transporter
protein GRAM domain containing 1B can coordinate cellular processes
by mediating cholesterol distribution between organelles, thereby
inhibiting autophagosome formation and reducing mitochondrial
bioenergetic metabolism (211).
Furthermore, cholesterol-rich membrane microstructure domain
(CEMM)-mediated sequestration of the vesicle-associated membrane
protein 3/syntaxin-6 complex inhibits autophagosome fusion.
Conversely, CEMM deficiency promotes autophagosome formation and
confers doxorubicin resistance in BC (212). Similarly, cholesterol inhibits
the autophagic degradation of receptor tyrosine kinase in a Golgi
membrane protein 1-dependent manner to promote HCC metastasis
(213). Cholesterol
accumulation in lysosomes induces autophagy initiation and enhances
carboplatin resistance in OV cells by activating the
NOTCH/DNA-binding protein recombination signal binding protein-Jκ
signaling pathway (214). These
results emphasize that cholesterol is an important regulator of
signaling pathways in cancer.
Cholesterol metabolites also play a key role in
activating autophagy. High 25-HC levels promote Kras-driven PDAC
progression. Mechanistically, 25-HC promotes autophagy, leading to
the downregulation of MHC-I and a reduction in CD8+
T-cell infiltration into tumors (215). BC is one of the most common
female cancer types in the world, with estrogen receptor-positive
BC being the most common subtype (216). The accumulation of
cholesterol-5,6-epoxide (5,6-EC) metabolites enhances resistance to
tamoxifen through the activation of autophagy to potentiate
antiestrogen binding site activity (217,218). Unraveling the molecular
interactions within the regulatory networks of cholesterol
metabolism and autophagy provides core guidance for identifying
novel anti-cancer targets and formulating targeted strategies
(Fig. 4).
EMT is a key driver of tumor growth and metastasis,
promoting a malignant phenotype by conferring enhanced metastatic
capacity and resistance to therapeutic interventions. Tumor EMT
states have also been found to exhibit high plasticity during
transitions between epithelial and mesenchymal phenotypes (219). The progression of EMT is
governed by the precise coordination of a core set of transcription
factors, such as Snail1/2, zinc finger enhancer-binding protein 1
and Twist1, whose expression levels directly determine the degree
of EMT activation and the transformation of cellular phenotypes
(220). Cholesterol increases
the risk of EMT in cancer. A high-cholesterol diet promotes lung
metastasis of HCC in mice by activating sterol
O-acyltransferase 1 (SOAT1)-mediated EMT. Mechanistically,
SOAT1 increases cholesterol accumulation and esterification,
thereby driving EMT and HCC progression (93). Treatment with 20 μmol/l
cholesterol was found to promote in vivo graft tumor growth
and distal metastasis in CRC by inducing EMT (19). Cholesterol has been demonstrated
to regulate several classical signaling pathways that activate EMT.
Cholesterol (10 μmol/l) induces adipocyte
membrane-associated protein binding to EGFR substrate 15-associated
protein, activates ERK1/2 and facilitates the EMT process in PC
cells (221). The integrity of
LRs is essential for the formation of the TGF-β receptor (TβR)
I/TβRII/TGF-β1 complex, and LR disruption impedes canonical TGF-β
signaling. Cholesterol within LRs promotes EMT, migration and
invasion in BC cells via TGF-β-mediated MAPK activation (222). High cholesterol also promotes
proliferation and migration in BC and PDAC cells through activation
of Wnt/β-catenin signaling (223,224), and similarly induces EMT in
melanoma via the MAPK pathway (225). Notably, our latest study
revealed that long-term treatment of OV cells with high cholesterol
concentrations (>20 μmol/l) significantly induces the
expression of cellular EMT transcription factors and mesenchymal
cell marker proteins. Mechanistically, cholesterol promotes
invasion of orthotopic ovarian tumors into the liver and kidney in
mice through activation of the PARP1/COL5A1/FAK/EMT axis (122). These studies collectively
indicated that cholesterol plays a key role in promoting EMT.
Cholesterol-related genes also have key roles in
EMT-induced metastasis and drug resistance. Upregulation of ABCA1
in CRC facilitates EMT induction and enhances the migratory and
invasive abilities by modulating caveolin-1 stability (226). High ABCG1 expression enhances
cisplatin resistance in LUAD by activating Slug-mediated EMT
(227). Dysregulation of
cholesterol metabolism not only promotes the development of HCC but
also drives tumors to exhibit highly invasive characteristics,
including intrahepatic spread and early extrahepatic metastasis
(76,228,229). A recent study has shown that
high expression of 7-DHC reductase is correlated with poor
prognosis in patients with BLCA and promotes metastasis in mice via
PI3K/AKT/mTOR-mediated EMT activation (230). 27-HC, the most abundant
oxysterol, increases the risk of BC progression by promoting EMT
and oncogenic transformation of BC stem cells through LXR
activation (15). Accumulation
of apolipoprotein E leads to cholesterol enrichment in HCC cells,
stimulating PI3K/AKT signaling, inducing EMT and increasing
sorafenib resistance and invasiveness (231). Aberrant HMGCR expression
enhances statin resistance in therapy-resistant PC cells and
augments TGF-β-induced EMT in lung and ovarian epithelial
carcinomas (232-234). Additionally, HMGCR augments
TGF/β-induced EMT progression in epithelial cell carcinomas (lung
and ovarian) (235).
Collectively, this scientific evidence highlights the important
role played by cholesterol in promoting EMT, providing a new means
of targeting cholesterol metabolism to combat tumor progression
(Fig. 5). Cholesterol-activated
EMT markers and transcription factors in different cancer types are
summarized in Table II.
Recent studies have demonstrated that modulation of
systemic cholesterol metabolism could improve responses to
immunotherapy (16,136,236). Cholesterol depletion is a key
metabolic basis for tumor-associated macrophages (TAMs) acquiring
an immunosuppressive phenotype (6). In patients with CRC, cholesterol
metabolism promotes macrophage polarization towards a pro-tumor
phenotype and is associated with poorer prognosis (237). Notably, replenishing
cholesterol or adding 7-DHC to mouse macrophages was shown to
inhibit interferon-β production (238). In a murine melanoma model,
cholesterol accumulation in the TME induced functional exhaustion
of CD8+ T cells (239). Cholesterol metabolism exhibits
different effects on different T cell subsets. Cholesterol enhances
receptor signaling and immune synapse formation in CD8+
T cells by binding to T cell receptor β (240). Another in vivo study
demonstrated that inhibition of ACAT1 by knockdown or
pharmacological inhibition can inhibit intracellular cholesterol
esterification in T cells and enhance the proliferative and
effector capacity of CD8+ T cells, whereas
CD4+ T cells are unaffected (241). In C57BL/6J mice, genes involved
in cholesterol esterification (ACAT1/2, lecithin cholesterol
acyltransferase and cholesterol ester transfer protein) and
utilization (CYP11A1, CYP17A1 and CYP7A1) are upregulated in γδ T
cells compared with αβ T cells (242). Moreover, cholesterol depletion
using methyl-β-cyclodextrin reduces the activation phenotype of γδ
T cells (243). However, the
impact of hypercholesterolemia or lipid-lowering treatments on T
cell signaling in human patients remains unclear.
Cholesterol has also been identified as a key
immunomodulatory factor, whose accumulation promotes tumor immune
escape. In the TME, cholesterol attenuates the efficacy of PD-L1
blockade by activating the signal transducer and activator of
transcription 3/nuclear factor κB pathway, driving macrophages
toward an M2-like phenotype that accelerates CRC progression
(244). Additionally,
cholesterol upregulates PD-L1 expression on cancer cells,
facilitating immune evasion (245,246). Hyaluronic acid oligomers
secreted by tumor cells increase cholesterol efflux from TAMs,
promoting M2 polarization and tumor progression (6). Although IL-9-secreting
CD8+ T cells (Tc9 cells) exhibit potent antitumor
activity, cholesterol suppresses IL-9 expression and impairs Tc9
cell function through LXR activation (247). In microsatellite-stable CRC,
tumor cells secrete distal cholesterol precursors that polarize T
cells into Th17 cells, promoting tumor growth (248).
Cholesterol derivatives similarly modulate immune
responses. 27-HC promotes the development of the BC pre-metastatic
microenvironment by attracting polymorphonuclear neutrophils and
γδ-T cells at metastatic sites and depleting CD8+ T
cells (249). Furthermore,
27-HC induces T cell cholesterol deficiency by inhibiting SREBP2
and activating LXR, leading to autophagy-mediated T cell apoptosis
(14). In HCC, oxidized sterols
activate LXRα in dendritic cells (DCs), downregulating CC chemokine
receptor 7 expression and impairing DC migration to lymphoid
organs, thereby suppressing antitumor immunity (250).
In summary, the conflicting results of cholesterol
in modulating immunotherapy suggest that a deeper understanding of
the regulatory mechanisms of cholesterol metabolism in the
interactions between tumor cells and immune cells in the TME will
contribute to the development of new cancer immunotherapy
strategies (Fig. 6). Targeting
cholesterol metabolism in the tumor immune microenvironment
represents a promising approach to enhance antitumor immunity.
Although extensive basic and preclinical studies
have demonstrated the involvement of cholesterol in cancer
development and the potential of targeting its metabolism, the
relationship between serum cholesterol levels and tumor risk
remains controversial, with epidemiological studies reporting
conflicting findings (3).
Several large-scale studies have indicated a positive association
between elevated serum cholesterol and cancer risk. For example,
two prospective cohort studies provided evidence that higher
cholesterol levels were positively associated with the risk of
high-grade PC (251,252). Another study revealed an
association between the use of statins to lower serum cholesterol
levels and the risk of developing or dying from 13 tumor types,
including HCC, MM, BC, ECa and CRC (253). A 10 mg/dl increase in
cholesterol was correlated with a 9% increase in PC recurrence
(128). In OV, elevated
preoperative LDL-C was significantly associated with a poorer OS,
whereas high HDL-C was correlated with improved progression-free
survival (254). Patients with
advanced-stage OV are typically accompanied by the presence of
malignant ascites (MAs) and high cholesterol levels in these MAs
(255). Moreover, high
cholesterol levels promote drug resistance in OV cells by
increasing the expression of multidrug resistance protein 1
(256). Dietary cholesterol and
tumor risk also deserve attention. According to population-based
cohort studies, tumorigenesis is closely related to dietary
structure (257), and changes
in dietary structure effectively prevent tumorigenesis and
progression (258,259). Increased dietary cholesterol
intake is positively associated with the risk of BC (260). Dietary cholesterol is a risk
factor for the development of ECa, with a 35% increased risk of
tumor development for every 150 mg/kcal of cholesterol consumed
(261). Esophageal cancer (EC)
ranks as the ninth most common cancer worldwide, with genetic
factors, dietary factors and environmental risk factors potentially
influencing its progression (262). A meta-analysis that
investigated the association between high-cholesterol diets and EC
revealed that dietary cholesterol intake may increase the risk of
EC (summarized odds ratio, 1.424; 95% CI, 1.191-1.704) (263). Pancreatic cancer (PCa) risk is
associated with elevated serum cholesterol levels, which are
partially influenced by diet (264). A study involving 258 patients
with PCa and 551 controls demonstrated that a plant-based
cholesterol-lowering diet is associated with a reduced risk of PCa
(265). In addition, higher
cumulative dietary cholesterol intake is positively associated with
the risk of GC (266), HCC
(267) and OV (267). The incidence of OV is
significantly lower by 40% in individuals consuming a
low-cholesterol diet than those on a conventional diet (268). However, studies on dietary
cholesterol and lung cancer risk have consistently shown no
correlation (115,269,270).
Conversely, other epidemiological studies reported
no clear association or even an inverse relationship between
cholesterol and cancer. For instance, a large prospective cohort
study from South Korea found that the association between serum TC
levels and cancer was dependent on the cancer type (251). Further comparison across cancer
types revealed that elevated serum TC levels showed a significant
positive association with the risk of PC and CRC in men, as well as
BC in women. Conversely, there was a significant negative
association with the overall risk of HCC and GC in the general
population. Moreover, a population-based cohort study has suggested
that serum TC levels may be negatively associated with the risk of
OV and that circulating lipid levels are not strongly correlated
with the risk of OV (271).
These studies showed that the positive correlation and negative
correlation coexisted, indicating that the association was cancer
type specific. Similarly, our latest study showed that higher daily
dietary cholesterol intake was significantly positively associated
with the risk of OV, whereas abnormal lipid levels were not
associated with the risk of OV (33).
These conflicting epidemiological results suggest
that the role of cholesterol in cancer development remains
uncertain, warranting further investigation into its underlying
mechanisms. Key issues include the reliability of dietary study
data, the limitations of animal models in simulating human disease
states and the potentially opposing effects of serum cholesterol
across different tumor stages. The current epidemiological evidence
regarding cholesterol and cancer risk is indeed contradictory,
stemming from multiple confounding factors and methodological
challenges. The primary concern is reverse causality: Actively
growing tumors consume large amounts of cholesterol to build
membrane structures and synthesize signaling molecules, potentially
leading to reduced serum cholesterol levels. Thus, observed low
cholesterol levels may result from undetected tumors rather than
cause them. This is particularly notable in studies of malignancies
such as liver and stomach cancer, potentially completely reversing
the apparent 'protective association' (272,273). Cancer type specificity further
complicates this relationship as metabolic dependencies vary
significantly across tumor types: Hormone-sensitive cancers such as
PC and OV may rely more heavily on cholesterol as a steroid hormone
precursor, showing positive correlations; whereas other tumor types
may exhibit no clear association or even negative correlations
(274,275). Methodological limitations also
warrant attention: Dietary cholesterol studies rely on
self-reporting, introducing recall bias; single serum cholesterol
measurements may fail to reflect long-term exposure levels; and
statin use confounds the association between serum cholesterol and
cancer risk. Most critically, correlation does not imply causation.
Observational studies reveal statistical associations but cannot
establish biological mechanisms. These conflicting findings suggest
systemic cholesterol levels may be unreliable cancer risk
indicators, while targeted interventions affecting intracellular
cholesterol metabolism may hold greater therapeutic promise than
systemic cholesterol reduction. Recently, we suggested that low
levels of cholesterol promote tumor progression, that high
cholesterol may inhibit tumor cell growth and that chronically high
levels of cholesterol ultimately screen for more proliferative and
invasive tumor cells (122).
Evidence from these studies suggests that the dysregulation of
cholesterol homeostasis is an important factor in cancer
development, but its true link to tumor progression remains
unclear. Studies are needed to link population epidemiological
data, molecular mechanisms and clinical data more broadly to more
effectively unravel the processes by which cholesterol affects
cancer. The associations of serum cholesterol and dietary
cholesterol with the risk of cancer development are summarized in
Table III.
The present review describes the role of
cholesterol in cancer progression from a multidimensional
perspective. First, how cholesterol activates oncogenes and
oncogenic signals was discussed. Then, the molecular mechanisms
regulated by cholesterol in cancer were summarized. Finally, the
ongoing controversies regarding cholesterol levels and cancer risk
within epidemiological studies were addressed. Although substantial
evidence supports a definitive role for cholesterol metabolism in
tumorigenesis and progression, several critical questions remain
unresolved. For example, whether the specific roles of cholesterol
metabolites or derivatives are consistent, what the causal
relationship is between abnormal cholesterol metabolism and
tumorigenesis and how cholesterol metabolism influences other
metabolic processes such as glucose metabolism. Notably, studies on
the heterogeneity of cholesterol metabolism (such single-cell
metabolomics) and comparative analyses across cancer types (such as
BC vs. liver cancer) are fewer and deserve focused attention. This
complexity suggests that not only do we need to modulate from a
single cholesterol metabolic pathway but also interfere with the
activation of oncogenes or oncogenic signals and that a combination
of different drugs or inhibitors may be a more effective antitumor
regimen.
In conclusion, dysregulation of cholesterol
metabolism is increasingly recognized as a critical facilitator of
cancer development. While population-based epidemiological findings
have been inconsistent, both basic and clinical studies indicate
that targeting cholesterol metabolism can significantly inhibit
tumor progression. These insights provide a robust foundation for
the development of cholesterol-focused therapeutics and offer
promising new strategies for cancer prevention and treatment.
Not applicable.
ZH was responsible for conceptualization, writing
the original draft and visualization. LZ and SG helped to revise
the manuscript and collect literature. GX and XY were responsible
for supervision, writing, reviewing and editing. Data
authentication is not applicable. All authors read and approved the
final version of the manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
This review was funded by the Research Fund of Sichuan Academy
of Medical Sciences and Sichuan Provincial People's Hospital (grant
no. 24QNPY025), in part by the Natural Science Foundation of
Sichuan Province (grant no. 2025YFHZ0308).
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