Fatty acid synthase (FASN) is a multifunctional homodimeric enzyme central to de novo fatty acid synthesis in mammals. Recent cryogenic electron microscopy (cryo-EM) studies have illuminated the structural basis of FASN catalysis, revealing multiple conformational states throughout the synthesis cycle. These findings show that the acyl carrier protein (ACP) domain dynamically shuttles substrates between spatially separated active sites, while the condensing and modifying regions remain structurally stable. In contrast to earlier models, FASN monomers operate asynchronously without large-scale domain rotations. Structural insights highlight critical ACP-domain interactions mediated by ionic contacts, offering new avenues for therapeutic targeting. Given its pivotal role in aberrant lipid metabolism, FASN has emerged as a promising drug target in cancer, metabolic disorders, and infectious diseases. Several inhibitors, including denifanstat, are currently in clinical trials. This review consolidates current knowledge of FASN structure–function relationships, emphasizing how cryo-EM discoveries inform rational drug design strategies focused on ACP-domain interactions and allosteric regulation.

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1. Paiva P, et al. Animal fatty acid synthase: a chemical nanofactory. Chem Rev. 2021;121:9502-9553. doi:10.1021/acs.chemrev.1c00147.
2. Ameer F, Scandiuzzi L, Hasnain S, Kalbacher H, Zaidi N. De novo lipogenesis in health and disease. Metabolism. 2014;63:895-902.
3. Batchuluun B, Pinkosky SL, Steinberg GR. Lipogenesis inhibitors: therapeutic opportunities and challenges. Nat Rev Drug Discov. 2022;21:283-305.
4. Ferraro GB, et al. Fatty acid synthesis is required for breast cancer brain metastasis. Nat Cancer. 2021;2:414-428.
5. Falchook G, et al. First-in-human study of the safety, pharmacokinetics, and pharmacodynamics of first-in-class fatty acid synthase inhibitor TVB-2640 alone and with a taxane in advanced tumors. EClinicalMedicine. 2021;34:100797.
6. Loomba R, et al. TVB-2640 (FASN inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled phase 2a trial. Gastroenterology. 2021;161:1475-1486.
7. Kelly KL, et al. De novo lipogenesis is essential for platelet production in humans. Nat Metab. 2020;2:1163-1178.
8. Bowers M, et al. FASN-dependent lipid metabolism links neurogenic stem/progenitor cell activity to learning and memory deficits. Cell Stem Cell. 2020;27:98-109.e11.
9. Grininger M. Enzymology of assembly line synthesis by modular polyketide synthases. Nat Chem Biol. 2023;19:401-415.
10. Lin Z, Li F, Krug PJ, Schmidt EW. The polyketide to fatty acid transition in the evolution of animal lipid metabolism. Nat Commun. 2024;15:236.
11. Jenke-Kodama H, Sandmann A, Müller R, Dittmann E. Evolutionary implications of bacterial polyketide synthases. Mol Biol Evol. 2005;22:2027-2039.
12. Nivina A, Yuet KP, Hsu J, Khosla C. Evolution and diversity of assembly-line polyketide synthases. Chem Rev. 2019;119:12524-12547.
13. Fischer M, Grininger M. Strategies in megasynthase engineering—fatty acid synthases (FAS) as model proteins. Beilstein J Org Chem. 2017;13:1204-1211.
14. Rittner A, et al. Probing the modularity of megasynthases by rational engineering of a fatty acid synthase type I. Protein Sci. 2019;28:414-428.
15. Rittner A, et al. Chemoenzymatic synthesis of fluorinated polyketides. Nat Chem. 2022;14:1000-1006.
16. Buyachuihan L, Reiners S, Zhao Y, Grininger M. The malonyl/acetyl-transferase from murine fatty acid synthase is a promiscuous engineering tool for editing polyketide scaffolds. Commun Chem. 2024;7:187.
17. Maier T, Jenni S, Ban N. Architecture of mammalian fatty acid synthase at 4.5 Å resolution. Science. 2006;311:1258-1262.
18. Maier T, Leibundgut M, Ban N. The crystal structure of a mammalian fatty acid synthase. Science. 2008;321:1315-1322.
19. Leibundgut M, Jenni S, Frick C, Ban N. Structural basis for substrate delivery by acyl carrier protein in the yeast fatty acid synthase. Science. 2007;316:288-290.
20. Singh K, et al. Reconstruction of a fatty acid synthesis cycle from acyl carrier protein and cofactor structural snapshots. Cell. 2023;186:5054-5067.e16.
21. Witkowski A, Joshi AK, Smith S. Characterization of the β-carbon processing reactions of the mammalian cytosolic fatty acid synthase: role of the central core. Biochemistry. 2004;43:10458-10466.
22. Witkowski A, Joshi AK, Smith S. Mechanism of the β-ketoacyl synthase reaction catalyzed by the animal fatty acid synthase. Biochemistry. 2002;41:10877-10887.
23. Rittner A, Paithankar KS, Huu KV, Grininger M. Characterization of the polyspecific transferase of murine type I fatty acid synthase (FAS) and implications for polyketide synthase (PKS) engineering. ACS Chem Biol. 2018;13:723-732.
24. Rangan VS, Joshi AK, Smith S. Mapping the functional topology of the animal fatty acid synthase by mutant complementation in vitro. Biochemistry. 2001;40:10792-10799.
25. Brink J, et al. Quaternary structure of human fatty acid synthase by electron cryomicroscopy. Proc Natl Acad Sci U S A. 2002;99:138-143.
26. Buyachuihan L, Stegemann F, Grininger M. How acyl carrier proteins (ACPs) direct fatty acid and polyketide biosynthesis. Angew Chem Int Ed. 2023.
27. Klaus M, et al. Solution structure and conformational flexibility of a polyketide synthase module. JACS Au. 2021;1:2162-2171.
28. Bunkoczi G, et al. Mechanism and substrate recognition of human holo ACP synthase. Chem Biol. 2007;14:1243-1253.
29. Izzo LT, et al. Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis. Sci Adv. 2023;9:eadf0115.
30. Chan DI, Vogel HJ. Current understanding of fatty acid biosynthesis and the acyl carrier protein. Biochem J. 2010;430:1-19.
31. Izzo LT, et al. Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis. Sci Adv. 2023;9:eadf0115.
32. Schultz K, Costa-Pinheiro P, Gardner L, Pinheiro LV, Ramirez-Solis J, Gardner SM, et al. Snapshots of acyl carrier protein shuttling in human fatty acid synthase. Nature. 2025;1-9.
33. Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, et al. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci U S A. 1994;91(14):6379-6383.
34. Zhang Y, Yang Z, Liu Y, Pei J, Li R, Yang Y. Targeting lipid metabolism: novel insights and therapeutic advances in pancreatic cancer treatment. Lipids Health Dis. 2025;24(1):12.
35. Kim DH, Song NY, Yim H. Targeting dysregulated lipid metabolism in the tumor microenvironment. Arch Pharm Res. 2023;46(11):855-881.
36. Khan F, Elsori D, Verma M, Pandey S, Obaidur Rab S, Siddiqui S, et al. Unraveling the intricate relationship between lipid metabolism and oncogenic signaling pathways. Front Cell Dev Biol. 2024;12:1399065.
37. He D, Sun X, Yang H, Li X, Yang D. TOFA induces cell cycle arrest and apoptosis in ACHN and 786-O cells through inhibiting PI3K/Akt/mTOR pathway. J Cancer. 2018;9(15):2734.
38. Liefwalker DF, Ryan M, Wang Z, Pathak KV, Plaisier S, Shah V, et al. Metabolic convergence on lipogenesis in RAS, BCR-ABL, and MYC-driven lymphoid malignancies. Cancer Metab. 2021;9(1):31.
39. Gao L, Xu Z, Huang Z, Tang Y, Yang D, Huang J, et al. CPI-613 rewires lipid metabolism to enhance pancreatic cancer apoptosis via the AMPK-ACC signaling. J Exp Clin Cancer Res. 2020;39(1):73.
40. Huang X, Pan L, Zuo Z, Li M, Zeng L, Li R, et al. LINC00842 inactivates transcription co-regulator PGC-1α to promote pancreatic cancer malignancy through metabolic remodelling. Nat Commun. 2021;12(1):3830.
41. Jamieson LE, Wetherill C, Faulds K, Graham D. Ratiometric Raman imaging reveals the new anti-cancer potential of lipid targeting drugs. Chem Sci. 2018;9(34):6935-6943.

Fatty acid synthase (FASN) is a multifunctional homodimeric enzyme central to de novo fatty acid synthesis in mammals. Recent cryogenic electron microscopy (cryo-EM) studies have illuminated the structural basis of FASN catalysis, revealing multiple conformational states throughout the synthesis cycle. These findings show that the acyl carrier protein (ACP) domain dynamically shuttles substrates between spatially separated active sites, while the condensing and modifying regions remain structurally stable. In contrast to earlier models, FASN monomers operate asynchronously without large-scale domain rotations. Structural insights highlight critical ACP-domain interactions mediated by ionic contacts, offering new avenues for therapeutic targeting. Given its pivotal role in aberrant lipid metabolism, FASN has emerged as a promising drug target in cancer, metabolic disorders, and infectious diseases. Several inhibitors, including denifanstat, are currently in clinical trials. This review consolidates current knowledge of FASN structure–function relationships, emphasizing how cryo-EM discoveries inform rational drug design strategies focused on ACP-domain interactions and allosteric regulation.

🔒 This is a subscription article

Full text is available to subscribers and institutional members. Please choose an option below to access it.

1. Paiva P, et al. Animal fatty acid synthase: a chemical nanofactory. Chem Rev. 2021;121:9502-9553. doi:10.1021/acs.chemrev.1c00147.
2. Ameer F, Scandiuzzi L, Hasnain S, Kalbacher H, Zaidi N. De novo lipogenesis in health and disease. Metabolism. 2014;63:895-902.
3. Batchuluun B, Pinkosky SL, Steinberg GR. Lipogenesis inhibitors: therapeutic opportunities and challenges. Nat Rev Drug Discov. 2022;21:283-305.
4. Ferraro GB, et al. Fatty acid synthesis is required for breast cancer brain metastasis. Nat Cancer. 2021;2:414-428.
5. Falchook G, et al. First-in-human study of the safety, pharmacokinetics, and pharmacodynamics of first-in-class fatty acid synthase inhibitor TVB-2640 alone and with a taxane in advanced tumors. EClinicalMedicine. 2021;34:100797.
6. Loomba R, et al. TVB-2640 (FASN inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled phase 2a trial. Gastroenterology. 2021;161:1475-1486.
7. Kelly KL, et al. De novo lipogenesis is essential for platelet production in humans. Nat Metab. 2020;2:1163-1178.
8. Bowers M, et al. FASN-dependent lipid metabolism links neurogenic stem/progenitor cell activity to learning and memory deficits. Cell Stem Cell. 2020;27:98-109.e11.
9. Grininger M. Enzymology of assembly line synthesis by modular polyketide synthases. Nat Chem Biol. 2023;19:401-415.
10. Lin Z, Li F, Krug PJ, Schmidt EW. The polyketide to fatty acid transition in the evolution of animal lipid metabolism. Nat Commun. 2024;15:236.
11. Jenke-Kodama H, Sandmann A, Müller R, Dittmann E. Evolutionary implications of bacterial polyketide synthases. Mol Biol Evol. 2005;22:2027-2039.
12. Nivina A, Yuet KP, Hsu J, Khosla C. Evolution and diversity of assembly-line polyketide synthases. Chem Rev. 2019;119:12524-12547.
13. Fischer M, Grininger M. Strategies in megasynthase engineering—fatty acid synthases (FAS) as model proteins. Beilstein J Org Chem. 2017;13:1204-1211.
14. Rittner A, et al. Probing the modularity of megasynthases by rational engineering of a fatty acid synthase type I. Protein Sci. 2019;28:414-428.
15. Rittner A, et al. Chemoenzymatic synthesis of fluorinated polyketides. Nat Chem. 2022;14:1000-1006.
16. Buyachuihan L, Reiners S, Zhao Y, Grininger M. The malonyl/acetyl-transferase from murine fatty acid synthase is a promiscuous engineering tool for editing polyketide scaffolds. Commun Chem. 2024;7:187.
17. Maier T, Jenni S, Ban N. Architecture of mammalian fatty acid synthase at 4.5 Å resolution. Science. 2006;311:1258-1262.
18. Maier T, Leibundgut M, Ban N. The crystal structure of a mammalian fatty acid synthase. Science. 2008;321:1315-1322.
19. Leibundgut M, Jenni S, Frick C, Ban N. Structural basis for substrate delivery by acyl carrier protein in the yeast fatty acid synthase. Science. 2007;316:288-290.
20. Singh K, et al. Reconstruction of a fatty acid synthesis cycle from acyl carrier protein and cofactor structural snapshots. Cell. 2023;186:5054-5067.e16.
21. Witkowski A, Joshi AK, Smith S. Characterization of the β-carbon processing reactions of the mammalian cytosolic fatty acid synthase: role of the central core. Biochemistry. 2004;43:10458-10466.
22. Witkowski A, Joshi AK, Smith S. Mechanism of the β-ketoacyl synthase reaction catalyzed by the animal fatty acid synthase. Biochemistry. 2002;41:10877-10887.
23. Rittner A, Paithankar KS, Huu KV, Grininger M. Characterization of the polyspecific transferase of murine type I fatty acid synthase (FAS) and implications for polyketide synthase (PKS) engineering. ACS Chem Biol. 2018;13:723-732.
24. Rangan VS, Joshi AK, Smith S. Mapping the functional topology of the animal fatty acid synthase by mutant complementation in vitro. Biochemistry. 2001;40:10792-10799.
25. Brink J, et al. Quaternary structure of human fatty acid synthase by electron cryomicroscopy. Proc Natl Acad Sci U S A. 2002;99:138-143.
26. Buyachuihan L, Stegemann F, Grininger M. How acyl carrier proteins (ACPs) direct fatty acid and polyketide biosynthesis. Angew Chem Int Ed. 2023.
27. Klaus M, et al. Solution structure and conformational flexibility of a polyketide synthase module. JACS Au. 2021;1:2162-2171.
28. Bunkoczi G, et al. Mechanism and substrate recognition of human holo ACP synthase. Chem Biol. 2007;14:1243-1253.
29. Izzo LT, et al. Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis. Sci Adv. 2023;9:eadf0115.
30. Chan DI, Vogel HJ. Current understanding of fatty acid biosynthesis and the acyl carrier protein. Biochem J. 2010;430:1-19.
31. Izzo LT, et al. Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis. Sci Adv. 2023;9:eadf0115.
32. Schultz K, Costa-Pinheiro P, Gardner L, Pinheiro LV, Ramirez-Solis J, Gardner SM, et al. Snapshots of acyl carrier protein shuttling in human fatty acid synthase. Nature. 2025;1-9.
33. Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, et al. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci U S A. 1994;91(14):6379-6383.
34. Zhang Y, Yang Z, Liu Y, Pei J, Li R, Yang Y. Targeting lipid metabolism: novel insights and therapeutic advances in pancreatic cancer treatment. Lipids Health Dis. 2025;24(1):12.
35. Kim DH, Song NY, Yim H. Targeting dysregulated lipid metabolism in the tumor microenvironment. Arch Pharm Res. 2023;46(11):855-881.
36. Khan F, Elsori D, Verma M, Pandey S, Obaidur Rab S, Siddiqui S, et al. Unraveling the intricate relationship between lipid metabolism and oncogenic signaling pathways. Front Cell Dev Biol. 2024;12:1399065.
37. He D, Sun X, Yang H, Li X, Yang D. TOFA induces cell cycle arrest and apoptosis in ACHN and 786-O cells through inhibiting PI3K/Akt/mTOR pathway. J Cancer. 2018;9(15):2734.
38. Liefwalker DF, Ryan M, Wang Z, Pathak KV, Plaisier S, Shah V, et al. Metabolic convergence on lipogenesis in RAS, BCR-ABL, and MYC-driven lymphoid malignancies. Cancer Metab. 2021;9(1):31.
39. Gao L, Xu Z, Huang Z, Tang Y, Yang D, Huang J, et al. CPI-613 rewires lipid metabolism to enhance pancreatic cancer apoptosis via the AMPK-ACC signaling. J Exp Clin Cancer Res. 2020;39(1):73.
40. Huang X, Pan L, Zuo Z, Li M, Zeng L, Li R, et al. LINC00842 inactivates transcription co-regulator PGC-1α to promote pancreatic cancer malignancy through metabolic remodelling. Nat Commun. 2021;12(1):3830.
41. Jamieson LE, Wetherill C, Faulds K, Graham D. Ratiometric Raman imaging reveals the new anti-cancer potential of lipid targeting drugs. Chem Sci. 2018;9(34):6935-6943.