APMAdvances in Precision Medicine2424-85922424-9106WHIOCE PUBLISHING PTE. LTD.10.18063/APM.v11i2.1411ArticleResearch Progress on Anti-Hepatocellular Carcinoma Therapy Targeting Lipid Metabolismhttps://artdesignp.com/journal/APM/11/2/10.18063/APM.v11i2.1411WangChenxi,LuNa20261122026-02-26 Lipid metabolic reprogramming is a critical characteristic in hepatocellular carcinoma (HCC) development and progression. Hepatoma cells reshape their metabolic patterns and tumor microenvironment by dysregulating fatty acid synthesis, uptake, and cholesterol metabolism, thereby promoting malignant progression and modulating treatment response. In recent years, targeting lipid metabolism pathways has emerged as a significant research direction in HCC therapy. This review systematically outlines key mechanisms of lipid metabolic reprogramming in HCC, focusing on emerging therapeutic strategies targeting critical pathways including cholesterol metabolism (HMGCR, SCAP, ACLY inhibitors), fatty acid metabolism (FABP5, FASN, ACC, CD36, lipoxygenase inhibitors), and sphingolipid metabolism (SphK2 and SMS1 inhibitors). Additionally, it discusses the potential and challenges of lipid metabolism-targeting agents in monotherapy and combination regimens, and prospects their clinical translation potential to provide a theoretical foundation for precision metabolic intervention in HCC.Hepatocellular carcinoma, Lipid metabolic reprogramming, Targeted therapy, Cholesterol metabolism, Fatty acid metabolism, Sphingolipid metabolism, Combination therapeutic strategy

[1] Yang JD, Hainaut P, Gores GJ, et al., 2019, A Global View of Hepatocellular Carcinoma: Trends, Risk, Prevention and Management. Nat Rev Gastroenterol Hepatol, 16(10): 589-604.[2] Ladd AD, Duarte S, Sahin I, et al., 2024, Mechanisms of Drug Resistance in HCC. Hepatology, 79(4): 926-940.[3] Yang F, Hilakivi-Clarke L, Shaha A, et al., 2023, Metabolic Reprogramming and Its Clinical Implication for Liver Cancer. Hepatology, 78(5): 1602-1624.[4] Foglia B, Beltrà M, Sutti S, et al., 2023, Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses. Int J Mol Sci, 24(8).[5] Khare T, Liu K, Chilambe LO, et al., 2025, NAFLD and NAFLD Related HCC: Emerging Treatments and Clinical Trials. Int J Mol Sci, 26(1).[6] Pham N, Benhammou JN, 2024, Statins in Chronic Liver Disease: Review of the Literature and Future Role. Semin Liver Dis, 44(2): 191-208.[7] Ricco N, Kron SJ, 2023, Statins in Cancer Prevention and Therapy. Cancers (Basel), 15(15).[8] Yang Y, Liu Y, Zou T, et al., 2025, HMGCR: A Malignancy Hub - Frontiers in Cancer Diagnosis and Therapy. Front Oncol, 15: 1698320.[9] Chandrasekaran P, Weiskirchen R, 2024, The Role of SCAP/SREBP as Central Regulators of Lipid Metabolism in Hepatic Steatosis. Int J Mol Sci, 25(2): 1109.[10] Li D, Yao Y, Rao Y, et al., 2022, Cholesterol Sensor SCAP Contributes to Sorafenib Resistance by Regulating Autophagy in Hepatocellular Carcinoma. J Exp Clin Cancer Res, 41(1): 116.[11] Cheng X, Li J, Guo D, 2018, SCAP/SREBPs Are Central Players in Lipid Metabolism and Novel Metabolic Targets in Cancer Therapy. Curr Top Med Chem, 18(6): 484-493.[12] Gholkar AA, Cheung K, Williams KJ, et al., 2016, Fatostatin Inhibits Cancer Cell Proliferation by Affecting Mitotic Microtubule Spindle Assembly and Cell Division. J Biol Chem, 291(33): 17001-17008.[13] Gu L, Zhu Y, Lin X, et al., 2021, The IKKβ-USP30-ACLY Axis Controls Lipogenesis and Tumorigenesis. Hepatology, 73(1): 160-174.[14] Gautam J, Wu J, Lally JSV, et al., 2025, ACLY Inhibition Promotes Tumour Immunity and Suppresses Liver Cancer. Nature, 645(8080): 507-517.[15] Granchi C, 2018, ATP Citrate Lyase (ACLY) Inhibitors: An Anti-cancer Strategy at the Crossroads of Glucose and Lipid Metabolism. Eur J Med Chem, 157: 1276-1291.[16] Xie Z, Zhang M, Song Q, et al., 2023, Development of the Novel ACLY Inhibitor 326E as a Promising Treatment for Hypercholesterolemia. Acta Pharm Sin B, 13(2): 739-753.[17] Yang X, Deng B, Zhao W, et al., 2025, FABP5(+) Lipid-Loaded Macrophages Process Tumour-Derived Unsaturated Fatty Acid Signal to Suppress T-Cell Antitumour Immunity. J Hepatol, 82(4): 676-689.[18] Tang B, Zhang X, Sun Y, et al., 2025, Tumor-Targeted FABP5/STING Cascade Promote Radiofrequency Ablation Induced Ferroptosis and Intratumoral Immune Rewiring in Hepatocellular Carcinoma. Adv Sci (Weinh), 12(45): e07864.[19] Sun J, Esplugues E, Bort A, et al., 2024, Fatty Acid Binding Protein 5 Suppression Attenuates Obesity-Induced Hepatocellular Carcinoma by Promoting Ferroptosis and Intratumoral Immune Rewiring. Nat Metab, 6(4): 741-763.[20] Che L, Paliogiannis P, Cigliano A, et al., 2019, Pathogenetic, Prognostic, and Therapeutic Role of Fatty Acid Synthase in Human Hepatocellular Carcinoma. Front Oncol, 9: 1412.[21] Huang J, Tsang WY, Fang XN, et al., 2024, FASN Inhibition Decreases MHC-I Degradation and Synergizes with PD-L1 Checkpoint Blockade in Hepatocellular Carcinoma. Cancer Res, 84(6): 855-871.[22] Xu XM, Deng JJ, Yuan GJ, et al., 2011, 5-Lipoxygenase Contributes to the Progression of Hepatocellular Carcinoma. Mol Med Rep, 4(6): 1195-1200.[23] Kahnt AS, Häfner AK, Steinhilber D, 2024, The Role of Human 5-Lipoxygenase (5-LO) in Carcinogenesis—A Question of Canonical and Non-Canonical Functions. Oncogene, 43(18): 1319-1327.[24] Morin P, Jr., Ferguson D, LeBlanc LM, et al., 2013, NMR Metabolomics Analysis of the Effects of 5-Lipoxygenase Inhibitors on Metabolism in Glioblastomas. J Proteome Res, 12(5): 2165-2176.[25] Bacci M, Lorito N, Smiriglia A, et al., 2024, Acetyl-CoA Carboxylase 1 Controls a Lipid Droplet-Peroxisome Axis and Is a Vulnerability of Endocrine-Resistant ER(+) Breast Cancer. Sci Transl Med, 16(736): eadf9874.[26] Yu Y, Nie Q, Wang Z, et al., 2023, Targeting Acetyl-CoA Carboxylase 1 for Cancer Therapy. Front Pharmacol, 14: 1129010.[27] Neokosmidis G, Cholongitas E, Tziomalos K, 2021, Acetyl-CoA Carboxylase Inhibitors in Non-Alcoholic Steatohepatitis: Is There a Benefit?. World J Gastroenterol, 27(39): 6522-6526.[28] Guerrero-Rodríguez SL, Mata-Cruz C, Pérez-Tapia SM, et al., 2022, Role of CD36 in Cancer Progression, Stemness, and Targeting. Front Cell Dev Biol, 10: 1079076.[29] Xia L, Zhou Z, Chen X, et al., 2023, Ligand-Dependent CD36 Functions in Cancer Progression, Metastasis, Immune Response, and Drug Resistance. Biomed Pharmacother, 168: 115834.[30] Mata-Cruz C, Guerrero-Rodríguez SL, Gómez-Castellano K, et al., 2025, Discovery and in Vitro Characterization of a Human Anti-CD36 scFv. Front Immunol, 16: 1531171.[31] Tzeng SF, Yu YR, Park J, et al., 2025, PLT012, a Humanized CD36-Blocking Antibody, Is Effective for Unleashing Antitumor Immunity Against Liver Cancer and Liver Metastasis. Cancer Discov, 15(8): 1676-1696.[32] Wang P, Yuan Y, Lin W, et al., 2019, Roles of Sphingosine-1-Phosphate Signaling in Cancer. Cancer Cell Int, 19: 295.[33] Marfe G, Mirone G, Shukla A, et al., 2015, Sphingosine Kinases Signalling in Carcinogenesis. Mini Rev Med Chem, 15(4): 300-314.[34] Luo Y, Xue H, Gao Y, et al., 2025, Sphingosine Kinase 2 in Cancer: A Review of Its Expression, Function, and Inhibitor Development. Int J Biol Macromol, 306(Pt 1): 141392.[35] Song K, Dai L, Long X, et al., 2019, Sphingosine Kinase 2 Inhibitor ABC294640 Displays Anti-Epithelial Ovarian Cancer Activities in Vitro and in Vivo. Onco Targets Ther, 12: 4437-4449.[36] Xun C, Chen MB, Qi L, et al., 2015, Targeting Sphingosine Kinase 2 (SphK2) by ABC294640 Inhibits Colorectal Cancer Cell Growth in Vitro and in Vivo. J Exp Clin Cancer Res, 34(1): 94.[37] Li Z, Hailemariam TK, Zhou H, et al., 2007, Inhibition of Sphingomyelin Synthase (SMS) Affects Intracellular Sphingomyelin Accumulation and Plasma Membrane Lipid Organization. Biochim Biophys Acta, 1771(9): 1186-1194.[38] Koh EH, Yoon JE, Ko MS, et al., 2021, Sphingomyelin Synthase 1 Mediates Hepatocyte Pyroptosis to Trigger Non-Alcoholic Steatohepatitis. Gut, 70(10): 1954-1964.[39] Lu H, Zhou L, Zuo H, et al., 2021, Overriding Sorafenib Resistance via Blocking Lipid Metabolism and Ras by Sphingomyelin Synthase 1 Inhibition in Hepatocellular Carcinoma. Cancer Chemother Pharmacol, 87(2): 217-228.