Fatty acid synthase in colorectal cancer prognosis via SP1/PLA2G4B axis implications for metastatic progression: a mechanistic and translational review
Keywords:
FASN, colorectal cancer, metabolic reprogramming, metastasis, prognostic biomarkerAbstract
Colorectal cancer remains a leading cause of cancer related mortality worldwide with metastatic progression representing the principal determinant of poor survival outcomes. Increasing evidence indicates that metabolic reprogramming, particularly enhanced de novo lipogenesis, plays a central role in tumor aggressiveness. This review explores the mechanistic and prognostic relevance of FASN in colorectal cancer, emphasizing its integration with SP1 and PLA2G4B in promoting metastatic dissemination. A structured literature review methodology was employed using Boolean operators AND and OR with keywords including “FASN,” “SP1,” “PLA2G4B,” “lipid metabolism,” “arachidonic acid signaling,” “colorectal cancer,” “metastasis,” and “prognostic biomarker.” The literature were conducted in PubMed, ScienceDirect, Springer Nature, and Google Scholar to ensure inclusion of high quality peer reviewed studies. The findings indicate that FASN mediated lipid synthesis contributes to membrane remodeling and oncogenic signaling activation, facilitating SP1 dependent transcriptional upregulation of PLA2G4B. Subsequent arachidonic acid signaling promotes inflammatory microenvironment modulation, epithelial mesenchymal transition, angiogenesis, and organ specific metastasis, particularly to the liver. The integrated FASN SP1 PLA2G4B axis is proposed as a coordinated pro metastatic signaling network rather than isolated molecular events. This review highlights the translational potential of targeting metabolic inflammatory crosstalk to improve prognostic stratification and therapeutic intervention strategies in colorectal cancer.
References
1. Garranzo-Asensio M, Rodríguez-Cobos J, Millán CS, Povés C, Fernández-Aceñero MJ, Pastor-Morate D. In-depth proteomics characterization of ΔNp73 effectors identifies key proteins with diagnostic potential implicated in lymphangiogenesis, vasculogenesis and metastasis in colorectal cancer. Mol Oncol. 2022. doi:10.1002/1878-0261.13228
2. Wu S, Zhang Y, Lin Z, Wei M. Global burden of colorectal cancer in 2022 and projections to 2050: incidence and mortality estimates from GLOBOCAN. 2025.
3. Zhang C, Zhang Y, Dong Y, Zi R, Wang Y, Chen Y. Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase-dependent EGFR palmitoylation. Cell Death Discov. 2024. doi:10.1038/s41420-023-01770-x
4. Jafari N, Drury J, Morris AJ, Onono FO, Stevens PD, Gao T, Liu J, Wang C, Lee EY, Weiss HL, Evers BM, Zaytseva YY. De novo fatty acid synthesis-driven sphingolipid metabolism promotes metastatic potential of colorectal cancer. Mol Cancer Res. 2019;17(1):140-152. doi:10.1158/1541-7786.MCR-18-0199
5. Tessmann JW, Zaytseva YY. Overexpression of fatty acid synthase increases exosomes secretion in colorectal cancer. Cancer Res. 2025. doi:10.1158/1538-7445.am2025-6575
6. Malapelle U. USP11 role in colorectal cancer growing and metastatisation. EBioMedicine. 2019. doi:10.1016/j.ebiom.2019.09.022
7. Zhu L, Feng J, Zhang X, Wei X, Ming C, Gao Y. The significance and diagnostic potential of CEA and FIB in colorectal cancer. iLabMed. 2025. doi:10.1002/ila2.70003
8. Xu Y, Wang X, Chu Y, Li J, Wang W, Hu X. Analysis of transcript-wide profile regulated by microsatellite instability of colorectal cancer. Ann Transl Med. 2022. doi:10.21037/atm-21-6126
9. Quan J, Cheng C, Tan Y, Jiang N, Liao C, Liao W. Acyl-CoA synthetase long-chain 3-mediated fatty acid oxidation is required for TGFβ1-induced epithelial-mesenchymal transition and metastasis of colorectal carcinoma. Int J Biol Sci. 2022. doi:10.7150/ijbs.69802
10. Nicolini A, Ferrari P. Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy. Front Immunol. 2024. doi:10.3389/fimmu.2024.1353787
11. Pang W, Li X, Yan S, Zhang J, Wu P, Yu H. Bufalin suppresses colorectal cancer liver metastasis by inhibiting de novo fatty acid synthesis via the PI3K/AKT-mediated SREBP1/FASN pathway. Molecules. 2025. doi:10.3390/molecules30173634
12. Park K, Garde A, Thendral SB, Soh AWJ, Chi Q, Sherwood DR. De novo lipid synthesis and polarized prenylation drive cell invasion through basement membrane. J Cell Biol. 2024. doi:10.1083/jcb.202402035
13. Grbčić P, Sedić M. Sphingosine 1-phosphate signaling and metabolism in chemoprevention and chemoresistance in colon cancer. Molecules. 2020;25(10):2436. doi:10.3390/molecules25102436
14. Wang Y, Wei Y, Bailey CM, Peng G, Zhang P, Wang Y. HIF1α integrates lipogenic FASN and glycolytic GLUT3 to overcome intratumor oxidative and hypoxic stress for colorectal cancer metastasis. 2025. doi:10.21203/rs.3.rs-5868429/v1
15. Zhang W, Yang H, Wang Z, Wu Y, Wang J, Duan G. miR-320a/SP1 negative reciprocal interaction contributes to cell growth and invasion in colorectal cancer. Cancer Cell Int. 2021. doi:10.1186/s12935-021-01874-3
16. Sun X, Xiao C, Wang X, Wu S, Yang Z, Sui B. Role of post-translational modifications of Sp1 in cancer: state of the art. Front Cell Dev Biol. 2024. doi:10.3389/fcell.2024.1412461
17. Wu X, Dong Z, Wang CJ, Barlow L, Fako V, Serrano M. FASN regulates cellular response to genotoxic treatments by increasing PARP-1 expression and DNA repair activity via NF-κB and SP1. Proc Natl Acad Sci U S A. 2016. doi:10.1073/pnas.1609934113
18. Yun S, Shin SW, Park J. Expression of fatty acid synthase is regulated by PGC-1α and contributes to increased cell proliferation. Oncol Rep. 2017. doi:10.3892/or.2017.6044
19. Esfahani AT, Mohammadpour S, Jalali P, Yaghoobi A, Karimpour R, Torkamani SS. Differential expression of angiogenesis-related genes VEGF and angiopoietin-1 in metastatic and EMAST-positive colorectal cancer patients. Sci Rep. 2024. doi:10.1038/s41598-024-61000-x
20. Ding M, Chen Y, Lang Y, Cui L. The role of cellular prion protein in cancer biology: a potential therapeutic target. Front Oncol. 2021. doi:10.3389/fonc.2021.742949
21. Chatterjee S, Kapila D, Dubey P, Pasunooti S, Tatavarthi S, Park C. The β-1,4 GalT-V interactome: potential therapeutic targets and a network of pathways driving cancer and cardiovascular and inflammatory diseases. Int J Mol Sci. 2025. doi:10.3390/ijms26168088
22. Tait S, Calura E, Baldassarre A, Masotti A, Varano B, Gessani S. Gene and lncRNA profiling of ω3/ω6 polyunsaturated fatty acid-exposed human visceral adipocytes uncovers different responses in healthy lean, obese and colorectal cancer-affected individuals. Int J Mol Sci. 2024. doi:10.3390/ijms25063357
23. Zhuang Z, Chen Y, Yao Y, Zhu X. Metabolic reprogramming in colorectal cancer: the impact of fatty acid metabolism. Hum Mutat. 2025. doi:10.1155/humu/9567214
24. Li M, Meng Y, Yao C, Zhao G. High glycolysis and lipid metabolism status predicts poor prognosis in colorectal cancer patients. Curr Mol Med. 2025. doi:10.2174/0115665240369037250319000043
25. Grunt TW, Lemberger L, Colomer R, López-Rodríguez ML, Wagner R. The pharmacological or genetic blockade of endogenous de novo fatty acid synthesis does not increase the uptake of exogenous lipids in ovarian cancer cells. Front Oncol. 2021. doi:10.3389/fonc.2021.610885
26. Xie S, Pan J, Xu J, Zhu W, Qin L. The critical function of metabolic reprogramming in cancer metastasis. Aging Cancer. 2022. doi:10.1002/aac2.12044
27. Jin Y, Chen Z, Dong J, Wang B, Fan S, Yang X. SREBP1/FASN/cholesterol axis facilitates radioresistance in colorectal cancer. FEBS Open Bio. 2021. doi:10.1002/2211-5463.13137
28. Drury J, Geisen ME, Tessmann JW, Rychahou P, Kelson CO, He D. Overexpression of fatty acid synthase upregulates glutamine–fructose-6-phosphate transaminase 1 and O-linked N-acetylglucosamine transferase to increase O-GlcNAc protein glycosylation and promote colorectal cancer growth. Int J Mol Sci. 2024. doi:10.3390/ijms25094883
