# Targeting Fatty Acids in Liver Cancer: Molecular Insights and Drug Approaches **Authors:** Antonio Cigliano, Dora Pischedda, Claudio Pandino, Grazia Galleri, Diego F. Calvisi PMC · DOI: 10.3390/biom16020329 · Biomolecules · 2026-02-20 ## TL;DR This paper reviews how fatty acid metabolism contributes to liver cancer progression and explores potential drug targets and therapies. ## Contribution The paper provides a comprehensive review of fatty acid metabolism's role in liver cancer and identifies novel therapeutic strategies. ## Key findings - Dysregulation of fatty acid metabolism promotes survival and proliferation of liver cancer cells. - Fatty acid metabolism influences immune cell function and tumor microenvironment. - Precision therapies targeting fatty acid metabolism could be integrated with current treatments. ## Abstract Primary liver cancer (PLC), commonly classified as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is a highly aggressive malignancy with a dismal prognosis. Recent research has highlighted the crucial role of dysregulation of fatty acid metabolism in HCC progression and therapeutic resistance. Here, with a focus primarily on HCC, we review how alterations in the processes involving fatty acids dynamically contribute to the survival, proliferation, and development of the drug resistance of PLC cells. In particular, increased expression of fatty acid transporters, reprogramming of de novo lipogenesis, and altered fatty acid oxidation trigger the upregulation of oncogenic signaling pathways and adaptation to nutrient-deprived conditions inducing the rapid proliferation of PLC cells. Furthermore, fatty acid metabolism influences immune cell function and angiogenesis, thereby shaping the tumor microenvironment and promoting the progression of PLC. This review explores the complex relationship between fatty acid metabolism and the progression of PLC. It discusses future directions regarding the most promising druggable targets and their current status in clinical trials. Furthermore, it examines the advancement of innovative therapeutic strategies and highlights the significant challenges in targeting fatty acid metabolism. Finally, it discusses how precision therapies focused on fatty acid metabolism can be effectively integrated with current treatments. ## Linked entities - **Diseases:** hepatocellular carcinoma (MONDO:0007256), intrahepatic cholangiocarcinoma (MONDO:0003210), liver cancer (MONDO:0002691) ## Full-text entities - **Genes:** ACSS2 (acyl-CoA synthetase short chain family member 2) [NCBI Gene 55902] {aka ACAS2, ACECS, ACS, ACSA, AceCS1, dJ1161H23.1}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, ACSL4 (acyl-CoA synthetase long chain family member 4) [NCBI Gene 2182] {aka ACS4, FACL4, LACS4, MRX63, MRX68, XLID63}, SOAT1 (sterol O-acyltransferase 1) [NCBI Gene 6646] {aka ACACT, ACAT, ACAT-1, ACAT1, SOAT, STAT}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, E2F1 (E2F transcription factor 1) [NCBI Gene 1869] {aka E2F-1, RBAP1, RBBP3, RBP3}, SCD (stearoyl-CoA desaturase) [NCBI Gene 6319] {aka FADS5, MSTP008, SCD1, SCDOS, hSCD1}, CASP1 (caspase 1) [NCBI Gene 834] {aka ICE, IL1BC, P45}, SLC27A1 (solute carrier family 27 member 1) [NCBI Gene 376497] {aka ACSVL5, FATP, FATP-1, FATP1}, HPGD (15-hydroxyprostaglandin dehydrogenase) [NCBI Gene 3248] {aka 15-PGDH, PGDH, PGDH1, PHOAR1, SDR36C1}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, FAS (Fas cell surface death receptor) [NCBI Gene 355] {aka ALPS1A, APO-1, APT1, CD95, FAS1, FASTM}, PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1) [NCBI Gene 5562] {aka AMPK, AMPK alpha 1, AMPKa1}, HDAC9 (histone deacetylase 9) [NCBI Gene 9734] {aka HD7, HD7b, HD9, HDAC, HDAC7B, HDAC9B}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, PPARA (peroxisome proliferator activated receptor alpha) [NCBI Gene 5465] {aka NR1C1, PPAR, PPAR-alpha, PPARalpha, hPPAR}, CBR1 (carbonyl reductase 1) [NCBI Gene 873] {aka CBR, PG-9-KR, SDR21C1, hCBR1}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, CTLA4 (cytotoxic T-lymphocyte associated protein 4) [NCBI Gene 1493] {aka ALPS5, CD, CD152, CELIAC3, CTLA-4, GRD4}, ACADM (acyl-CoA dehydrogenase medium chain) [NCBI Gene 34] {aka ACAD1, MCAD, MCADH}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, FASN (fatty acid synthase) [NCBI Gene 2194] {aka FAS, OA-519, SDR27X1}, KEAP1 (kelch like ECH associated protein 1) [NCBI Gene 9817] {aka INrf2, KLHL19}, KSR1 (kinase suppressor of ras 1) [NCBI Gene 8844] {aka KSR, RSU2}, TERT (telomerase reverse transcriptase) [NCBI Gene 7015] {aka CMM9, DKCA2, DKCB4, EST2, PFBMFT1, TCS1}, MLXIPL (MLX interacting protein like) [NCBI Gene 51085] {aka CHREBP, MIO, MONDOB, WBSCR14, WS-bHLH, bHLHd14}, E2F2 (E2F transcription factor 2) [NCBI Gene 1870] {aka E2F-2}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, MAPK8 (mitogen-activated protein kinase 8) [NCBI Gene 5599] {aka JNK, JNK-46, JNK1, JNK1A2, JNK21B1/2, PRKM8}, PTGR1 (prostaglandin reductase 1) [NCBI Gene 22949] {aka DIG-1, LTB4DH, PGR1, ZADH3}, CPT1C (carnitine palmitoyltransferase 1C) [NCBI Gene 126129] {aka CATL1, CPT I-C, CPT1-B, CPT1P, CPTI-B, CPTIC}, MIR26A1 (microRNA 26a-1) [NCBI Gene 407015] {aka MIR26A, MIRN26A1, mir-26a-1}, HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) [NCBI Gene 3156] {aka LDLCQ3, LGMDR28, MYPLG}, SEC63 (SEC63 protein translocation regulator) [NCBI Gene 11231] {aka DNAJC23, ERdj2, PCLD2, PRO2507, SEC63L}, PZP (PZP alpha-2-macroglobulin like) [NCBI Gene 5858] {aka CPAMD6}, FABP5 (fatty acid binding protein 5) [NCBI Gene 2171] {aka E-FABP, EFABP, KFABP, PA-FABP, PAFABP}, BCO2 (beta-carotene oxygenase 2) [NCBI Gene 83875] {aka B-DIOX-II, BCDO2}, LOX (lysyl oxidase) [NCBI Gene 4015] {aka AAT10}, MAPK14 (mitogen-activated protein kinase 14) [NCBI Gene 1432] {aka CSBP, CSBP1, CSBP2, CSPB1, EXIP, Mxi2}, ACACA (acetyl-CoA carboxylase alpha) [NCBI Gene 31] {aka ACAC, ACACAD, ACACalpha, ACC, ACC1, ACCA}, CPT2 (carnitine palmitoyltransferase 2) [NCBI Gene 1376] {aka CPT1, CPTASE, IIAE4}, PNLIP (pancreatic lipase) [NCBI Gene 5406] {aka PL, PNLIPD, PTL}, PSME3 (proteasome activator subunit 3) [NCBI Gene 10197] {aka HEL-S-283, Ki, PA28-gamma, PA28G, PA28gamma, REG-GAMMA}, LIPA (lipase A, lysosomal acid type) [NCBI Gene 3988] {aka CESD, LAL}, LIPE (lipase E, hormone sensitive type) [NCBI Gene 3991] {aka AOMS4, FPLD6, HSL, LHS, REH}, ACOX1 (acyl-CoA oxidase 1) [NCBI Gene 51] {aka ACOX, AOX, MITCH, PALMCOX, SCOX}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, CDKN1B (cyclin dependent kinase inhibitor 1B) [NCBI Gene 1027] {aka CDKN4, KIP1, MEN1B, MEN4, P27KIP1}, LPAR1 (lysophosphatidic acid receptor 1) [NCBI Gene 1902] {aka EDG2, Gpcr26, LPA1, Mrec1.3, VZG1, edg-2}, PNPLA2 (patatin like domain 2, triacylglycerol lipase) [NCBI Gene 57104] {aka 1110001C14Rik, ATGL, FP17548, PEDF-R, TTS-2.2, TTS2}, TXNRD1 (thioredoxin reductase 1) [NCBI Gene 7296] {aka GRIM-12, TR, TR1, TRXR1, TXNR, TXNR1}, CD274 (CD274 molecule) [NCBI Gene 29126] {aka ADMIO5, B7-H, B7H1, PD-L1, PDCD1L1, PDCD1LG1}, SNAI1 (snail family transcriptional repressor 1) [NCBI Gene 6615] {aka SLUGH2, SNA, SNAH, SNAIL, SNAIL1, dJ710H13.1}, DNASE2 (deoxyribonuclease 2, lysosomal) [NCBI Gene 1777] {aka AIPCS, DNASE2A, DNL, DNL2}, LTB4R2 (leukotriene B4 receptor 2) [NCBI Gene 56413] {aka BLT2, BLTR2, JULF2, KPG_004, LTB4-R 2, LTB4-R2}, SREBF2 (sterol regulatory element binding transcription factor 2) [NCBI Gene 6721] {aka SREBP-2, SREBP2, bHLHd2}, PLA2G4A (phospholipase A2 group IVA) [NCBI Gene 5321] {aka GURDP, PLA2G4, cPLA2, cPLA2-alpha}, SKP2 (S-phase kinase associated protein 2) [NCBI Gene 6502] {aka FBL1, FBXL1, FLB1, p45}, MIR21 (microRNA 21) [NCBI Gene 406991] {aka MIRN21, hsa-mir-21, miR-21, miRNA21}, AWAT1 (acyl-CoA wax alcohol acyltransferase 1) [NCBI Gene 158833] {aka DGA2, DGAT2L3} - **Diseases:** insulin resistance (MESH:D007333), acidosis (MESH:D000138), weight (MESH:D015431), cytotoxic (MESH:D064420), cholestasis (MESH:D002779), infections (MESH:D007239), viral hepatitis (MESH:D014777), colon cancer (MESH:D015179), tumorigenic (MESH:D002471), carcinogenic (MESH:D011230), CPS1 deficiency (MESH:D007153), death (MESH:D003643), metastases (MESH:D009362), excess (MESH:D006970), hypertriglyceridemia (MESH:D015228), PSC (MESH:D015209), solid (MESH:D018250), CCA (MESH:C536211), liver tumors (MESH:D008113), glioblastoma (MESH:D005909), astrocytoma (MESH:D001254), Tumor-associated macrophage (MESH:D000072716), LDs (MESH:D011017), Hepatocellular (MESH:D006528), FAO (MESH:C536560), ovarian cancer (MESH:D010051), liver (MESH:D017093), hepatic diseases (MESH:D056486), breast and colorectal cancer (MESH:D001943), alcoholic liver disease (MESH:D008108), HBV and (MESH:D006509), CHC (MESH:D019698), diabetes (MESH:D003920), Cancer (MESH:D009369), multiple myeloma (MESH:D009101), NAFLD (MESH:D065626), alcohol abuse (MESH:D000437), hyperlipidemia (MESH:D006949), cirrhosis (MESH:D005355), melanoma (MESH:D008545), prostate cancer (MESH:D011471), injury to (MESH:D014947), Fatty Acid Catabolism (MESH:D008067), Inflammatory (MESH:D007249), chronic hepatitis (MESH:D006521), MASLD (MESH:D008107), hypoxia (MESH:D000860), hepatocyte damage (MESH:D020263), NSCLC (MESH:D002289), nasopharyngeal cancer (MESH:D009303), Metabolic (MESH:D008659), ICC (MESH:D018281), carcinogenesis (MESH:D063646), oral carcinoma (MESH:D009062), gastric cancer (MESH:D013274), TAM (MESH:D020914), hypoxic (MESH:D002534), NASH (MESH:D005235), lung adenocarcinoma (MESH:D000077192), obese (MESH:D009765) - **Chemicals:** MUFA (MESH:D005229), TVB-3166 (MESH:C000615719), carbohydrate (MESH:D002241), cerulenin (MESH:D002569), FA (MESH:D005227), pravastatin (MESH:D017035), PC (MESH:D010713), cholesteryl esters (MESH:D002788), flavin adenine dinucleotide (MESH:D005182), acylcarnitine (MESH:C116917), Bempedoic acid (MESH:C581236), NADPH (MESH:D009249), amino acids (MESH:D000596), LTs (MESH:D015289), Orlistat (MESH:D000077403), vorinostat (MESH:D000077337), glycerol (MESH:D005990), TG (MESH:D013866), PUFA (MESH:D005231), atorvastatin (MESH:D000069059), Firsocostat (MESH:C000629250), palmitoyl-carnitine (MESH:D010172), LTB4 (MESH:D007975), palmitate (MESH:D010168), palmitoleic acid (MESH:C008757), bile acids (MESH:D001647), FASCINIT (-), EICs (MESH:D015777), monoacylglycerol (MESH:D050178), ROS (MESH:D017382), folate (MESH:D005492), FADH2 (MESH:C058805), sphingosine (MESH:D013110), glucose (MESH:D005947), C16-ceramide (MESH:C097760), simvastatin (MESH:D019821), DAG (MESH:D004075), alcohol (MESH:D000438), ABC294640 (MESH:C548780), GSK2194069 (MESH:C000592442), oleic acid (MESH:D019301), LPC (MESH:D008244), Sphingolipid (MESH:D013107), DEN (MESH:D004052), NAD + (MESH:D009243), -Hydroxybutyrate (MESH:D006885), palmitic acid (MESH:D019308), VLCFA (MESH:C017364), lignoceric acid (MESH:C010210), sucrose (MESH:D013395), MK1775 (MESH:C549567), Lipid (MESH:D008055), citrate (MESH:D019343), reduced glutathione (MESH:D005978), glycodeoxycholate (MESH:D006002), glutamine (MESH:D005973), fructose (MESH:D005632), ATP (MESH:D000255), TCA (MESH:D014233), etomoxir (MESH:C054207) - **Species:** Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116], B virus [taxon 37962], Mus musculus (house mouse, species) [taxon 10090] ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12937817/full.md ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12937817/full.md ## References 206 references — full list in the complete paper: https://tomesphere.com/paper/PMC12937817/full.md --- Source: https://tomesphere.com/paper/PMC12937817