Lipid metabolism reprogramming drives malignant proliferation and invasiveness in hepatocellular carcinoma (HCC). Lipids also function as signalling molecules modulating tumour epigenetics and the microenvironment. This review summarises key alterations in lipid metabolism in HCC, examines how lipid shifts in immune and stromal cells promote HCC, and discusses therapeutic potential.
Introduction
HCC is the sixth most common cancer globally. Metabolic-associated HCC has doubled over two decades and is projected to rise further. Altered lipid metabolism is a pivotal driver. HCC cells upregulate lipid uptake, de novo lipogenesis (DNL), and fatty acid oxidation (FAO). Lipids also act as membrane components and signalling mediators; palmitic acid (PA) regulates HCC epigenetically. Lipophagy controls lipid droplet (LD) turnover, influencing invasion, metastasis, and drug resistance. Lipid metabolism also remodels the tumour microenvironment (TME), fostering immunosuppression. Most HCC patients are diagnosed at advanced stages; lipid metabolism is a key determinant of treatment efficacy.
Lipid Metabolism Reprogramming in HCC
Lipid uptake: CD36 and FABPs are pivotal transporters. CD36 activates Src/PI3K/Akt/mTOR, promoting growth and metastasis, and selectively promotes MUFA uptake. FABP5 activates HIF-1, upregulating lipid storage genes and suppressing β-oxidation; its inhibition renders HCC cells susceptible to ferroptosis.
Lipid synthesis: DNL provides biosynthetic materials and energy; high DNL gene expression correlates with poorer survival. Key enzymes include ACC, ACLY, FASN, and SCD1. SCD1 increases the MUFA/SFA ratio, enhancing invasion. ACLY inhibition enhances antitumour immunity and lenvatinib efficacy. ACSS2 mediates epigenetic modifications; high ACSS2 correlates with lower malignancy.
Enhanced DNL leads to phospholipid, PA, and cholesterol accumulation. Phosphatidylcholine (PC) synthesis is elevated, correlating with inflammation. MUFA-containing PC suppresses ferroptosis; inhibition increases sorafenib sensitivity. PA activates ER stress and oxidative stress; palmitoylation via ZDHHC proteins regulates oncogenic signalling.
Cholesteryl ester (CE) metabolism features enhanced synthesis and esterification. SOAT1 converts free cholesterol to CEs for LD storage. SREBP2 is the master regulator; its inhibition attenuates CE synthesis and synergises with sorafenib. Paradoxically, inhibiting CE synthesis can activate arachidonic acid metabolism, driving HCC.
Lipophagy: PPARα-mediated lipophagy may promote advanced HCC. Lipophagy inhibition promotes chemoresistance via LD accumulation. Under glutamine deprivation, lipophagy preserves redox homeostasis.
Lipid Metabolism and the TME
T cells: Lipid accumulation drives CD8⁺ T-cell exhaustion via JNK/STAT, PI3K/Akt/mTOR, and STAT3. CD36-mediated lipid uptake induces ferroptosis in CD8⁺ T cells. FAO supports CD8⁺ T-cell function; excessive FAO impairs it. Treg recruitment is enhanced via the CCL20/CCR6 axis; CD36 inhibition synergises with anti-PD-1.
NK/NKT cells: Long-chain acylcarnitine accumulation suppresses NKT proliferation. CE accumulation promotes lipid peroxidation, impairing NKT function. Elevated serum CE enhances NK activity in mice.
TAMs: Lipid accumulation promotes M1-to-M2 polarisation. oxLDL and CE polarise TREM2⁺ TAMs, promoting invasion and CD8⁺ T-cell dysfunction. CD36 and FABPs mediate lipid uptake; FABP5 promotes M2 polarisation via PPARγ. M2 TAMs depend on FAO and express PD-L1. FAO inhibition steers TAMs toward antitumour phenotype.
CAFs: Pro-tumorigenic CAFs upregulate FASN, ACC, and SCD1. CAF-secreted lipids promote tumour growth. CD36⁺ CAFs express MIF, suppressing T-cell immunity. CAF-derived exosomes enhance proliferation, metastasis, and drug tolerance. Exosomal HSPC111 reprograms CAF lipid metabolism; exosomal miR-522 suppresses ferroptosis.
Drug Development
Targeting CD36: anti-CD36 antibody PLT012 blocks metabolic reprogramming in Tregs and CD8⁺ TILs; VT1021 has entered clinical trials. Targeting DNL: FASN inhibition elevates MHC class I expression, synergising with immune checkpoint inhibitors; orlistat sensitises sorafenib-resistant HCC. SCD1 inhibition synergises with TKIs. ACLY and ACC inhibitors suppress HCC. Targeting CE metabolism: statins show promise; simvastatin re-sensitises HCC to sorafenib. Nanoparticle delivery enhances efficacy.
Clinical trials: PLT012 is in a phase I trial and received FDA Fast Track designation. VT1021 showed a 42.9% disease control rate. Statins in HCC showed mixed results: early studies showed survival benefit; later trials yielded less consistent results.
Limitations
Most trials had small sample sizes and heterogeneity. Statins have broad effects, and effective intratumoral exposure remains unclear. CD36-targeted strategies remain at an early stage. Statins require further validation in HCC combination strategies.
Conclusions
Tumour progression is accompanied by altered lipid metabolism, supporting HCC through energy supply and modulation of tumour behaviour. Lipid reprogramming also fosters an immunosuppressive microenvironment. Targeting lipid metabolism is promising; inhibitors of CE synthesis and lipid biosynthetic enzymes show synergistic effects with antitumour drugs. However, compensatory mechanisms and immune cell metabolic integrity remain challenges. More high-quality studies are needed to translate preclinical advances into clinical benefit.
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The study was recently published in the Journal of Clinical and Translational Hepatology .
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Journal of Clinical and Translational Hepatology
Advances in Lipid Metabolism Reprogramming in Hepatocellular Carcinoma
26-Jun-2026