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Abstract

Colorectal cancer ranks among the most prevalent and lethal malignant tumors globally. Historically, the incidence of colorectal cancer in China has been lower than that in developed European and American countries; however, recent trends indicate a rising incidence due to changes in dietary patterns and lifestyle. Lipids serve critical roles in human physiology, such as energy provision, cell membrane formation, signaling molecule function, and hormone synthesis. Dysregulation of lipid metabolism is strongly associated with various metabolic disorders, including cardiovascular disease, obesity, hepatic steatosis, and diabetes, as well as tumor initiation, progression, and metastasis. Lipid metabolism significantly contributes to cancer development by facilitating biofilm synthesis, supplying substrates for biomass production, and activating signaling pathways linked to cancer cell proliferation and migration. This narrative review summarizes recent advancements in understanding the regulation of lipid metabolism in colorectal cancer, evaluates potential molecular targets, and highlights relevant clinical trials. All relevant literature was retrieved through a comprehensive search of the PubMed database.

Keywords

Colorectal cancer lipid metabolism fatty acids cholesterol lipid droplets

Introduction

Colorectal cancer (CRC) is one of the most prevalent malignant tumors globally. According to the latest global cancer statistics, CRC ranks third in both incidence and mortality rates.¹ Historically, the incidence of CRC in China was significantly lower than in developed European and American countries.² However, in recent years, due to changes in dietary patterns and lifestyle among residents, the incidence of CRC in China has gradually increased.²

Lipids play critical roles in the body, including supplying energy,³ building cell membranes,^4,5 functioning as signaling molecules, and participating in hormone synthesis.⁶ Glycolipids and phospholipids (which include phosphoglycerides and sphingolipids), along with cholesterol, constitute the primary building blocks of biological membranes.⁵ Additionally, cholesterol acts as a precursor for fat-soluble vitamins and steroid hormones. Fatty acids (FAs), as the main constituents of glycolipids and phospholipids, can partially esterify with glycerol to generate triglycerides, a type of nonpolar lipid that accumulates in lipid droplets when nutrients are abundant. Under energy stress conditions, these triglycerides undergo hydrolysis through fatty acid oxidation (FAO, or beta-oxidation) to produce ATP (Figure 1). Beyond their roles in energy production and membrane assembly, lipids serve as signaling molecules derived from the breakdown of membrane lipids by phospholipases and the synthesis of essential fatty acids, with their availability largely determined by dietary lipids.^7,8

Figure 1.

Lipid metabolic synthesis and decomposition.

Disruptions in lipid metabolism are linked to the development of multiple metabolic disorders, such as cardiovascular disease,⁹ obesity,¹⁰ hepatic steatosis,¹¹ and diabetes.¹² Lipid metabolism also plays a pivotal role in tumorigenesis, progression, metastasis, and the regulation of cancer immunity.¹³ This is evidenced by its involvement in biofilm synthesis,⁵ supplying raw materials for biomass generation,¹⁴ and activation of complex signaling pathways associated with cancer cell growth and migration (Figure 2). In this review, we summarize recent advancements in the regulation of lipid metabolism in colorectal tumors and explore potential molecular targets for colorectal tumor-associated lipid therapy.

Figure 2.

Molecular mechanisms and targeting strategies for colorectal cancer (CRC).

Abnormal lipid metabolism in colorectal cancer

Increased lipid uptake

CD36 is a fatty acid translocation enzyme predominantly expressed in the human gastrointestinal tract, responsible for absorbing long-chain fatty acids and oxidized low-density lipoprotein.¹⁵ During tumor growth, production, and metabolism are highly active, creating a high demand for energy and oxygen within the tumor microenvironment (TME).¹⁶ A recent study comparing 458 normal tissues with 349 tumor tissues revealed significantly reduced CD36 expression in tumor tissues, supporting the aforementioned findings.¹⁷

Research by Yang-AnWen et al. further indicated that adipocytes in the TME may alter the energy homeostasis and cellular metabolism of colorectal cancer cells via AMP-activated Protein Kinase (AMPK) activation.¹⁸ CD36 inhibits glycolysis mediated by ubiquitinated β-catenin/c-Myc of glypican-4 (GPC4), suppressing downstream aerobic glycolysis.¹⁹ Current literature confirms that CD36 upregulation occurs in tumor-associated macrophages (TAMs) within the TME,²⁰ where TAMs transport large quantities of lipids through CD36 for lipid oxidation, thereby promoting tumor metabolism.²¹ Analysis of the Cancer Genome Atlas demonstrated that increased CD36 expression correlates with high epithelial-mesenchymal transition (EMT) across all cancers.²² CD36 is highly expressed in metastasis-initiating cells (MICs), providing energy for tumor metastasis via fatty acid uptake and inducing EMT through Wnt/β-catenin and transforming growth factor β (TGF-β) signaling pathways.²³ Additional studies using radiotracer assays showed that fatty acid transport proteins (FATPs) and CD36 mediate uptake of fatty acid analogs in CRC cells, with inhibition suppressing this process.²⁴ Furthermore, bile acid metabolism-related gene risk models including CD36 can predict immune microenvironment characteristics and chemotherapy response in patients with CRC.²⁵

These findings collectively demonstrate CD36's dual roles in CRC—exhibiting tumor-suppressive properties in some contexts while promoting tumor progression in others. This complex behavior of CD36 suggests that therapeutic strategies for CRC must account for its cell type-specific roles. While CD36 exhibits tumor-suppressive functions in epithelial cells by inhibiting glycolysis and mediating the degradation of oncogenic proteins such as β-catenin and c-Myc, its upregulation in TAMs and MICs promotes lipid oxidation and activates pro-metastatic pathways. Therefore, a tailored approach is essential: therapies targeting CD36 in epithelial cells should aim to preserve its tumor-suppressive effects, while treatments for the stromal compartment, particularly TAMs and MICs, should focus on inhibiting CD36's pro-tumorigenic functions. Such precision-based strategies could enhance treatment efficacy and minimize potential adverse effects, offering a more effective way to manage CRC at various stages of progression.

Abnormal fatty acid metabolism

The observation that most fatty acids in malignant cells originate from de novo adipogenesis, irrespective of extracellular lipid availability, underscores the significance of upregulated endogenous lipid biosynthesis in malignant transformation.²⁶ Fatty acid synthase (FASN), a polymorphic enzyme protein, serves as a key regulator of de novo lipid synthesis.²⁷ FASN is the most targeted among lipogenic genes due to its overexpression in cancer cells^28,29 and its significant antiapoptotic effects, which have been detected in primary CRC and colorectal liver metastases (CRLM).³⁰ Overexpression of FASN increases glutamine—fructose-6-phosphate transaminase 1 (GFPT1) and O-Linked NAcetylglucosamine (O-GlcNAc) Transferase (OGT) expression and O-GlcNAcylation levels, thereby promoting CRC progression.³¹ Additionally, FASN promotes antiniding-apoptosis resistance in colorectal liver metastases via the extracellular signal-regulated kinase (ERK)1/2 pathway.³² Intriguingly, FASN inhibition exerts a more detrimental effect on tumor growth in vivo, potentially due to compensatory mechanisms such as dietary fatty acid intake. Upregulation of the fatty acid transporter CD36 and enhanced exogenous lipid uptake can compensate for pharmacological or genetic FASN inhibition.³³ Conversely, FASN inhibition weakens CD44-related signaling and reduces CRC metastasis.³³

Fatty acid binding proteins (FABPs) function as intracellular fatty acid carriers, coordinating lipid responses and playing roles in cellular fatty acid utilization while being closely associated with metabolic and inflammatory pathways. Recent studies have demonstrated that FABPs contribute to CRC progression through diverse mechanisms. Functional investigations have revealed that FABP5 is epigenetically activated in metastatic CRC via promoter hypomethylation and nuclear factor kappa-B (NF-κB)-dependent transcriptional regulation, forming a positive feedback loop with IL-8 secretion to sustain constitutive NF-κB signaling.³⁴ Although this study did not experimentally validate FABP5's direct involvement in fatty acid transport, its findings regarding epigenetic dysregulation provide novel insights into FABP-mediated CRC metastasis. Complementary bioinformatics analyses have shown significant overexpression of the bile acid transporter FABP6 in CRC tissues, which correlates with poor patient prognosis.³⁵ While these findings reveal distinct roles of different FABP isoforms in CRC pathogenesis (FABP5 in metastatic signaling and FABP6 in bile acid metabolism), their specific contributions to lipid metabolic reprogramming in CRC remain to be elucidated. FABP5 inhibits CRC progression through mTOR-mediated autophagy by reducing FASN expression.³⁶ FABP4 promotes colon cancer cell migration and invasion by regulating fatty acid transport and activating AKT Serine/Threonine Kinase (also known as Protein Kinase B, PKB) (AKT) and EMT pathways.³⁷

FASN combines malonyl-CoA and acetyl-CoA to produce the saturated fatty acid palmitate. The acyl-CoA synthetase (ACS)/stearoyl-CoA desaturase (ACSL/SCD) network enhances CRC cell invasion and migration through EMT.³⁸ In xenograft mouse models, SCD1 silencing or inhibition reduces CRC generation.³⁹ Chen demonstrated that SCD-1 enhances CRC invasion and metastasis capabilities and promotes tumor progression by facilitating EMT.⁴⁰

ACSL catalyzes the synthesis of long-chain fatty acids into fatty acyl-CoA, critical for neutral fat, phospholipid, and lipoprotein modifications and fatty acid β-oxidation.⁴¹ Although the ACSL family participates in similar responses, they differ in substrate specificity, subcellular localization, and tissue distribution, implicating them in cancer development.⁴² ACSL4 promotes colorectal cancer cell proliferation, whereas miR-19b-1-3p exhibits protective effects, reflecting the role of the ACSL/SCD axis in CRC progression.⁴³ Vargas et al.'s experiments further elucidate this genetically.⁴⁴

Acetyl-CoA carboxylase (ACC) is a crucial regulatory enzyme in lipid metabolism that catalyzes the formation of malonyl-CoA from acetyl-CoA, representing the rate-limiting step of de novo lipogenesis.⁴⁵ As a potent allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT1), blocking mitochondrial uptake of long-chain fatty acids and thereby promoting lipid accumulation under nutrient-rich conditions.⁴⁶

Recent studies have shown that Arctigenin alleviates the progression of colitis-associated cancer (CAC) in mice by inhibiting CPT1-mediated fatty acid oxidation (FAO), thereby disrupting the assembly of NOD-, LRR- and pyrin domain-containing protein (NLRP3) inflammasomes in macrophages .⁴⁷ These findings highlight CPT1's role in modulating immune responses and shaping the inflammatory microenvironment, thereby indirectly influencing tumor development.

Acyl-CoA oxidase-1 (ACOX1), the first and rate-limiting enzyme in FAO and a major H2O2 producer in peroxisomes,⁴⁸ is downregulated in CRC, promoting tumor progression.⁴⁹ In CRC, sirtuin 5 (SIRT5)-mediated desuccinylation of succinate dehydrogenase complex subunit C (SDHC) increases ACOX1 succinylation and activity. Inhibiting SDHC restores ACOX1 suppression by activating the PI3 K/AKT pathway, while recent studies have shown that SDHC downregulation is also linked to the inhibition of CPT1A expression, leading to reduced FAO rates.⁵⁰ In contrast, CPT1, the rate-limiting enzyme in mitochondrial β-oxidation, transports fatty acids into mitochondria for energy production.⁴⁶ Although ACOX1 and CPT1 operate in distinct subcellular compartments (peroxisomes vs. mitochondria), they collaboratively orchestrate cellular fatty acid catabolism.

Abnormal triglyceride metabolism

Lipotriglyceride lipase (ATGL), also known as PNPLA2, is a lipid droplet lactate dehydrogenase (LD)-related rate-limiting enzyme specifically responsible for LD utilization by breaking down stored triglycerides.^51,52 ATGL inhibition reduces carcinogenic MYC proto-oncogene, BHLH transcription factor (MYC) and increases tumor suppressor forkhead box O3 (FOXO3).⁵³ Obesity enhances colon tumor occurrence by increasing ATGL-mediated LD utilization in colon cancer cells and stem cells.⁵³ Arylacetamide deacetylase (AADA), homologous to hormone-sensitive lipase (official gene name: LIPE) (HSL),⁵⁴ protects metastatic CRC cells from ferroptosis by inhibiting lipid peroxidation in a SLC7A11-dependent manner.⁵⁵

Obesity leads to insulin and insulin-like growth factor (IGF) overexpression, activating the PI3 K/Akt signaling pathway, enhancing cell survival and growth, and amplifying carcinogenic effects.⁵⁶ The IGF-1 signaling pathway maintains long-term health in many organisms, comprising two IGFs (IGF-1 and IGF-2)^57,58 and six IGF-binding proteins (IGFBP-1-6).⁵⁹ IGFBP proteins⁶⁰ and interacting molecules⁶¹ belong to the tyrosine kinase receptor family. IGF-1 induces cytoplasmic degradation of the tumor suppressor gene P53, leading to uncontrolled cell proliferation and tumor formation.⁶² Williams et al. analyzed that IGFBP3 enhances p53-dependent cell apoptosis after DNA damage and confirmed that IGFBP3 deletion promotes colorectal adenoma development.⁶³ Insulin and IGF overexpression in obese patients activates the PI3 K/Akt signaling pathway, improving cell survival and growth and amplifying carcinogenic effects.⁵⁶

Abnormal cholesterol metabolism

ATP-citrate lyase (ACLY), a downstream target of sterol regulatory element-binding proteins (SREBPs), catalyzes the conversion of citrate to acetyl-CoA, thereby providing essential precursors for both fatty acid synthesis and cholesterol biosynthesis .⁶⁴ ACLY also contributes to histone acetylation via phosphorylation-dependent mechanisms, promoting transcriptional programs that drive tumor progression .⁶⁵ Elevated ACLY expression and activity have been associated with enhanced cancer cell proliferation and metastasis .⁶⁶ For instance, exosomal HSPC111 has been shown to promote CRC liver metastasis by increasing acetyl-CoA levels and ACLY phosphorylation .⁶⁷

The synthesis of acetyl-CoA from cholesterol through de novo pathways is critical for supporting tumor growth and progression.⁶⁸ Key enzymes in cholesterol biosynthesis, such as HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), farnesyl diphosphate synthase (FDPS), and geranylgeranyl diphosphate synthase 1 (GGPS1), underscore the therapeutic potential of inhibiting cholesterol production alongside conventional chemotherapy to improve outcomes in colon cancer treatment.⁶⁹

Sterol regulatory element-binding protein 2 (SREBP-2) controls the expression of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the primary regulatory enzyme in cholesterol biosynthesis. SREBP2 inhibition has been explored as an anticancer therapy.⁷⁰ Hepatocyte growth factor （HGF）-activated Met signaling not only upregulates SREBP2 to promote tumor cell survival but also recruits numerous antitumor neutrophils, partially counteracting Met's carcinogenic effects. Thus, Met may exhibit a bidirectional trend as an upstream anticancer target of cholesterol.⁷¹

Abnormal SREBP1 expression is involved in CRC regulation. Comparisons between cancer and adjacent tissue samples from patients with CRC revealed significant SREBP1 upregulation in cancer tissues, activating NF-κB via reactive oxygen species (ROS) to promote matrix metalloproteinase-7 (MMP-7) expression,⁷² a metallostromal enzyme associated with high CRC invasiveness.⁷³ Based on radiation stimulation responses of two SREBP proteins, SREBP1 may relate to CRC radioresistance and drug resistance, serving as a target to regulate CRC patient radiotherapy sensitivity.⁷⁴

Low-density lipoprotein receptor (LDLR), widely found on cell surfaces, improves cholesterol transport efficiency.⁷⁵ LDLR upregulation on CRC cell surfaces correlates positively with lymphatic and distant metastasis risks and mediates ROS production by promoting cholesterol accumulation.⁷⁶ Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol transport by reducing LDLR recycling via lysosome-targeted receptor destruction.⁷⁷ One study showed that PCSK9 inhibition reduced circulating cholesterol levels via liver cell uptake and transformation, inhibiting colon tumor growth in mice.⁷⁸ Recent studies indicate that PCSK9 inhibition promotes major histocompatibility complex I (MHC I) upregulation on cancer cells, attracting more CD8+ T cells to kill tumors.^79–81

Interactions among fatty acid, triglyceride, and cholesterol metabolic pathways and their impact on colorectal cancer progression

Fatty acid, cholesterol, and triglyceride metabolism are intricately interconnected and play a crucial roleCRC progression. FASN overexpression accelerates fatty acid production and enhances the activity of HMGCR, a key enzyme in cholesterol biosynthesis. This promotes cholesterol synthesis, contributing to membrane stability and assembly in rapidly proliferating cancer cells.²⁶ Cholesterol accumulation alters membrane fluidity, activates signaling pathways, and feedback-induces FASN expression, further enhancing fatty acid synthesis to maintain membrane stability and support tumor proliferation and invasion.⁶⁸

Fatty acid metabolism is also closely linked to triglyceride metabolism. Adipose triglyceride lipase (ATGL) breaks down triglycerides into fatty acids and glycerol, providing energy for tumor cells. ATGL overexpression correlates with increased CRC cell proliferation and invasion.^51,53 However, excessive fatty acid accumulation can inhibit ATGL activity, reducing triglyceride breakdown, which stabilizes cell membranes and promotes tumor cell growth. Obesity exacerbates CRC progression by enhancing ATGL activity, further accelerating cancer development.^52,53

Similarly, cholesterol and triglyceride metabolism are interrelated. Cholesterol accumulation not only affects membrane fluidity and stability but also promotes triglyceride synthesis. This process is likely mediated by changes in membrane properties, which enhance the activity of fatty acid synthesis and oxidation enzymes, thereby modulating triglyceride metabolism.^68,76 Additionally, HMGCR activity can feedback-regulate key enzymes in triglyceride metabolism, influencing the overall metabolic state of tumor cells and enhancing their adaptability under hypoxic or nutrient-deficient conditions.^71,76

Moreover, cholesterol's effect extends beyond membrane stability to include the promotion of triglyceride synthesis. Cholesterol accumulation alters membrane properties, facilitating fatty acid synthesis and oxidation, which regulates triglyceride metabolism. ATP-citrate lyase (ACLY) plays a pivotal role in this process by producing acetyl-CoA, a precursor for both fatty acid and cholesterol synthesis. Elevated ACLY activity is associated with increased CRC cell proliferation and metastasis, underscoring its importance in CRC progression.^71–74

Key enzymes such as FASN, fatty acid binding proteins (FABP), acyl-CoA synthetases (ACSL), and acyl-CoA oxidase-1 (ACOX1) significantly influence CRC progression. FABP5 and FABP6 regulate fatty acid transport and inflammatory pathways to promote CRC metastasis, while ACSL4 enhances cancer cell migration and invasion. Together, these enzymes enable CRC cells to adapt their lipid metabolism to meet the metabolic demands required for rapid proliferation and metastasis.

The clinical value of abnormal lipid metabolism and colorectal cancer

According to a European cohort study, the Metabolic Syndrome (MetS) scores for body mass index (BMI), blood pressure, blood glucose levels, total cholesterol, and triglycerides were found to be significantly positively correlated with the risk of colorectal cancer in both men and women.⁸² High BMI was more strongly associated with colon cancer than with rectal cancer, and this correlation was stronger in men than in women.⁸³ Two large Swedish cohorts further supported these findings; however, subgroup analysis of CRC contradicted the notion that low plasma adiponectin or high BMI in women was associated with a higher risk of Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated CRC.⁸⁴

Nevertheless, two recent Mendelian randomization (MR) studies have presented conflicting results. Henry et al. reported an association between a higher genetic score of total cholesterol (TC) and an increased risk of CRC but did not find a significant association between low-density lipoprotein (LDL), high-density lipoprotein (HDL), or triglycerides (TG).⁸⁵ In contrast, Gemma et al. ruled out all causal associations between lipids and CRC.⁸⁶

It is important to note that CRC encompasses two major sites: the colon and the rectum. Previous studies have demonstrated that colon and rectal cancers differ not only in anatomical location but also in molecular mechanisms, risk factors, diagnosis, and prognosis.⁸⁷ Recently, cheese consumption has been associated with protection against CRC, particularly proximal colon cancer, suggesting that the cheese hypothesis may exert differential effects on colon and rectal cancer.⁸⁸

Targeting lipid metabolism to treat colorectal cancer

The synthesis and crosstalk between carcinogenic signaling pathways and metabolic reprogramming of lipids promote the expansion, survival, dissemination, and metastatic spread of cancer cells. Dysregulated lipid metabolism in both malignant cells and stromal components of the tumor microenvironment (such as immune cells, adipocytes, endothelial cells, and fibroblasts) exhibits complex regulatory networks and functional interdependence. Current research focuses on developing therapeutic strategies targeting different aspects of lipid metabolism (Table 1).

Table 1.

Representative targets within the lipid metabolism pathway for anti-CRC drug clinical trial.

Target protein	Inhibitor	Clinical trial	Type of cancer	References
HMGCR	XELIRI/FOLFIRI plus simvastatin	Phase III	Colorectal cancer	NCT01238094⁹⁰
	Simvastatin plus Capecitabine-cisplatin	Phase III	Colorectal cancer	NCT01099085⁹¹
	Simvastatin plus FOLFIRI	Phase II	Colorectal cancer	100
FASN	TVB-2640	Phase II	Solid malignant tumors	NCT02223247
	TVB-3166	Preclinical	Colorectal cancer	⁹³
SCD	Betulinic acid	Preclinical	Colorectal cancer	¹⁰¹

CDC: colorectal cancer; FASN: fatty acid synthase, HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase; SCD: stearoyl-CoA desaturase.

To inhibit cholesterol biogenesis, statins (HMGCR antagonists) have been extensively studied. Epidemiological analyses reveal that statin use correlates with improved prognosis in patients with CRC receiving conventional chemotherapy.⁸⁹ Conversely, prospective phase III clinical trials evaluating pravastatin or simvastatin as adjuncts to standard regimens in metastatic colorectal/gastric cancer failed to demonstrate therapeutic superiority.^90,91 It has been suggested that lipophilic statins more readily enter extrahepatic cells, whereas hydrophilic statins are more liver-selective.⁹² Additionally, clinical evidence indicates that statins’ antineoplastic effects require optimized dosing schedules and prolonged administration.⁹¹ Thus, discovering predictive biomarkers for precision medicine approaches, including optimal statin selection, dosage, and treatment duration, could enhance their utility as combination therapy.

To target fatty acid (FA) synthesis, two inhibitors, TVB-3166 and TVB-2640, FASN. TVB-3166 has completed preclinical testing and demonstrated inhibition of FASN to suppress tumor development,⁹³ while TVB-2640 is currently being evaluated in a phase II clinical trial targeting solid tumors.

In addition to FA synthesis, recent studies have highlighted the importance of fatty acid oxidation (FAO) in CRC progression. The key FAO enzyme carnitine palmitoyltransferase 1A (CPT1A) is overexpressed in CRC cells, where it facilitates mitochondrial fatty acid oxidation to generate energy and eliminate ROS, contributing to anoikis resistance and enhanced metastatic potential. Clinical data indicate that CPT1A expression is significantly elevated in metastatic lesions compared to primary tumors.⁹⁴ Targeting CPT1A using small-molecule inhibitors such as DHP-B—a plant-derived compound that covalently binds to its active site—has shown potent antitumor effects in both in vitro and in vivo CRC models.⁹⁵ Furthermore, upstream regulators such as nuclear-localized valosin-containing protein (VCP) can promote transcription of CPT1A and other FAO-related genes by degrading HDAC1, increasing tumor FAO dependency. Inhibitors of VCP, particularly when combined with metabolic agents like metformin, have demonstrated synergistic antitumor efficacy in CRC.⁹⁶

Lipid metabolism is a key regulator of the tumor immune microenvironment. A prognostic model based on lipid metabolism (LMrisk), which includes genes like CYP19A1, has been shown to predict the response to immunotherapy in colon cancer. CYP19A1, a steroidogenic enzyme involved in lipid signaling, is positively correlated with Programmed Cell Death Ligand 1 (PD-L1) expression and immune cell infiltration, while negatively associated with CD8⁺ T cell levels. Inhibiting CYP19A1 with agents like letrozole or siRNA reduces PD-L1, IL-6, and TGF-β levels via GPR30-AKT signaling, restoring CD8⁺ T cell-mediated antitumor responses and enhancing the efficacy of anti-PD-1 therapy in preclinical models.⁹⁷ These findings suggest a promising strategy of combining lipid metabolism inhibition with immune checkpoint blockade to enhance therapeutic outcomes in CRC.

Bevacizumab resistance in CRC also involves lipid metabolic reprogramming within the TME. Extracellular matrix (ECM) stiffening triggers lipolysis in hepatic stellate cells (HSCs), which release free fatty acids via the focal adhesion kinase (FAK) / yes-associated protein (YAP) signaling pathway. These fatty acids activate FAO in cancer cells, thereby promoting resistance to treatment.⁹⁸ Targeting this pathway using FAO inhibitors (e.g. etomoxir) or FAK/YAP blockers has shown potential in reversing resistance.

Moreover, in obese patients with CRC, adipose-derived exosomes have been shown to carry microsomal triglyceride transfer protein (MTTP), which forms a complex with PRAP1 to reduce polyunsaturated fatty acid (PUFA) levels and suppress ferroptosis. This process decreases sensitivity to oxaliplatin, as demonstrated in both organoid and mouse models.⁹⁹ Inhibiting MTTP or promoting ferroptosis may therefore help overcome therapy resistance in obese individuals.

Conclusion

Lipid metabolism in cancer is regulated by both oncogenic pathways and the tumor microenvironment (TME), with bidirectional crosstalk promoting tumor progression, immune evasion, and therapy resistance. Targeting key regulators like CD36, FASN, and FAO may improve outcomes. Therapeutic strategies, including statins, FASN inhibitors, and lipid metabolism modulators, show promise but require further validation. Understanding cell type-specific and tumor subtype-specific lipid metabolism is essential to minimize side effects and enhance therapeutic efficacy.

Future perspectives

Recent studies have demonstrated that lipid metabolism in cancer cells is regulated by both intracellular oncogenic signaling pathways and multiple components of the tumor microenvironment (TME), including cytokines, growth factors, and extracellular nucleic acids. Conversely, dysregulated lipid metabolism can reshape signaling pathways through lipid-mediated secretory molecules and influence surrounding cells, forming a complex bidirectional regulatory network during cancer progression. Therefore, elucidating the lipid metabolic network and its interaction with the TME is crucial for advancing our understanding of tumor biology.

Moreover, lipid metabolism exhibits notable heterogeneity across different cell types. Certain molecules, such as CD36, may exert dual functions depending on the cell type, while inhibition of fatty acid synthase (FASN) can lead to enhanced uptake of exogenous lipids by cancer cells. These findings highlight the need to consider cell type-specific roles and compensatory mechanisms when designing lipid-targeted therapies.

The interconnected metabolism of fatty acids, triglycerides, and cholesterol constitutes a central axis that supports tumor growth, metastasis, and therapeutic resistance. Lipid metabolic reprogramming also facilitates immune evasion, ferroptosis resistance, and failure of antiangiogenic therapies, indicating an urgent need to develop strategies that disrupt these adaptive processes.

Therapeutically, multiple lipid metabolic targets are currently under preclinical or clinical investigation. Statins, which inhibit cholesterol biosynthesis, have shown potential survival benefits in retrospective studies of patients with colorectal cancer receiving chemotherapy; however, results from randomized clinical trials remain inconsistent, possibly due to differences in statin type, dosage, and patient stratification. FASN inhibitors, such as TVB-2640, have entered clinical evaluation and demonstrated promising antitumor activity in early studies. Reprogrammed fatty acid oxidation (FAO) is associated with resistance to antiangiogenic agents like bevacizumab, and targeting FAO or its upstream regulators (e.g. FAK/YAP) may help restore treatment sensitivity.

Additionally, lipid metabolism directly shapes the tumor immune microenvironment. For instance, CYP19A1-mediated regulation of PD-L1 expression contributes to immune evasion, suggesting that targeting lipid metabolism may enhance the efficacy of immune checkpoint inhibitors. In obesity-associated CRC, exosomal MTTP has been shown to promote oxaliplatin resistance by inhibiting ferroptosis, indicating a potential role for lipid metabolic intervention in overcoming chemotherapy resistance.

In summary, further research into oncogenic regulation, post-translational modification, and structural features of lipid metabolic enzymes will facilitate the development of precision therapies that address dysregulated lipid metabolism rather than broadly inhibiting metabolic pathways. Investigating the heterogeneity of lipid metabolism among CRC subtypes—particularly between colon and rectal cancers—may also provide new opportunities for subtype-specific and less toxic therapeutic strategies.

Footnotes

Acknowledgements

The authors would like to thank all collaborators who provided valuable input during the preparation of this review. Additionally, the authors acknowledge the use of AI tools, including ChatGPT (OpenAI), which assisted in language refinement and formatting support during manuscript preparation.

ORCID iDs

Jinhui Zha

Yonghao Zhong

Authors’ contribution

All authors contributed to the article and approved the submitted version. JZ contributed to the initial framework of the manuscript, prepared the figures, and tables. PC was responsible for drafting the manuscript. YZ contributed to writing and revising the manuscript. RL revised the manuscript and verified the accuracy of literature citations. GF served as the corresponding author and supervised the overall work.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: GF is supported by the National Natural Science Foundation of China (82471623, 82001489).

Declaration of conflicting interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The role and mechanism of abnormal lipid metabolism in colorectal cancer

Abstract

Keywords

Introduction

Abnormal lipid metabolism in colorectal cancer

Increased lipid uptake

Abnormal fatty acid metabolism

Abnormal triglyceride metabolism

Abnormal cholesterol metabolism

Interactions among fatty acid, triglyceride, and cholesterol metabolic pathways and their impact on colorectal cancer progression

The clinical value of abnormal lipid metabolism and colorectal cancer

Targeting lipid metabolism to treat colorectal cancer

Conclusion

Future perspectives

Footnotes

Acknowledgements

ORCID iDs

Authors’ contribution

Funding

Declaration of conflicting interests

References