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).

SREBPs, as key regulators of cholesterol metabolism (59), contribute to establishing energy and lipid reserves in tumor cells, playing a crucial role in tumor proliferation, stemness and drug resistance (60). In GBM cells, SREBP1 promotes lipid droplet autophagy by regulating key autophagy genes (such as autophagy-related protein 9B, autophagy-associated gene 4A and light chain 3B), leading to cholesterol ester hydrolysis and the release of cholesterol into lysosomes, ultimately promoting tumor growth (61). Patients with HCC have a poor prognosis and are prone to drug resistance (62). The liver is the primary organ for cholesterol metabolism, and abnormal cholesterol levels are closely associated with the progression of HCC. A previous study has revealed that SREBP1 enhances monounsaturated fatty acid synthesis by upregulating stearoyl-CoA desaturase 1, thereby suppressing ferroptosis in HCC cells and promoting xenograft tumor invasion and sorafenib resistance in mice (63). Notably, Su and Koeberle (64) conducted a systematic review on the role of SREBP1 in HCC progression, metastasis and drug resistance. The review mainly summarized that SREBP1 is an independent prognostic indicator for overall survival (OS) and disease-free survival in patients with HCC. SREBP1 can also regulate signaling pathways in tumor cells, including the PI3K-AKT-mTOR axis, protein kinase A (PKA), c-Myc and Janus kinase (JAK). Moreover, SREBPs have been shown to be upregulated in the tissues of patients with PC (65), BC (66) and OV (67).

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).

Notably, statins also enhance the efficacy of conventional antitumor drugs (165). Retrospective studies have shown that statin therapy prolongs survival in patients with BC (166), HCC (167), CRC (168) and metastatic PC (169) treated with a combination of first-line chemotherapeutic agents. Results from a phase II clinical trial demonstrated that combining SIM with the epidermal growth factor receptor (EGFR) inhibitor, gefitinib, yielded superior antitumor effects compared with gefitinib alone in non-small cell lung cancer (NSCLC).

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.