image: Tumor progression is frequently accompanied by alterations in lipid metabolism, primarily involving enhanced pathways such as lipid uptake, synthesis, and FAO. These upregulated pathways support HCC through dual mechanisms. First, they supply the energy and metabolic building blocks required for rapid proliferation. Second, the resulting metabolite overaccumulation further modulates tumor behavior, driving proliferation, metastasis, and invasion through mechanisms such as plasma membrane remodeling, epigenetic reprogramming, and disruption of redox homeostasis. As investigations into HCC deepen, it has become evident that lipid metabolic reprogramming not only propels intrinsic tumor progression but also modulates stromal and immune cells within the TME. Excessive lipid accrual and augmented FAO foster an immunosuppressive microenvironment by impairing T-cell antitumor effector functions, promoting M2 macrophage polarization, and activating CAFs, thereby facilitating HCC immune evasion. Consequently, targeting lipid metabolism to suppress HCC progression represents a promising avenue of research. In recent years, studies on lipid metabolism have proliferated, with interventions targeting lipid metabolism demonstrating favorable therapeutic outcomes in HCC. Several relevant targets have been identified. In studies combining these targets with antitumor agents, they show potential to inhibit tumor progression and overcome chemoresistance. Inhibitors of CE synthesis, such as statins, along with suppressors of key lipid biosynthetic enzymes, exhibit synergistic effects with concomitant antitumor drugs and can even resensitize HCC cells to certain chemotherapeutics. Nevertheless, given the intricate metabolic milieu of HCC, direct perturbation of metabolic pathways may elicit compensatory mechanisms and compromise the metabolic integrity of associated immune cells. Thus, substantial challenges persist in the development of targeted therapeutics directed at metabolic pathways. While clinically approved metabolism-targeted therapies are still limited, the rapidly evolving understanding of lipid metabolism and tumor immunometabolic crosstalk holds significant promise. This knowledge is poised to identify novel therapeutic targets with high specificity and favorable toxicity profiles. Clinical trials targeting lipid metabolism in cancer remain exploratory, likely because of the complexity of lipid metabolic regulatory networks. More high-quality studies are needed to further elucidate the regulatory network of lipid metabolism in HCC. Building on current clinical evidence, future studies may require larger and more precisely selected patient populations closely associated with lipid metabolic alterations, together with more rigorous trial designs. Preclinical studies of lipid metabolism in HCC have shown considerable promise; however, many challenges still need to be addressed before these advances can translate into broad clinical benefit for most patients. Figures were created with BioRender (https://www.biorender.com/). This work was financially supported by Leading Talents in Science and Technology Innovation in Hunan Province (2024RC1051) (to LSL); Natural Science Fund for Outstanding Young Scholars of Hunan Province (2024JJ2037/2023JJ60027) (to LSL); Project of Hunan Provincial Health Commission (Z2023031) (written as initials “to LSL”); and Frontiers Diagnosis and Treatment of Liver Cancer Innovation Team (KCT202404) (to LSL); Scientific Research Project of the Hunan Provincial Education Department (24B0099) (to JQ); Scientific Research Project of the Hunan Provincial Education Department (25C0027) (to DWQ).Declarations
Acknowledgement
Funding
Credit: Sulai Liu, Yu Peng
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
Journal of Clinical and Translational Hepatology
Article Title
Advances in Lipid Metabolism Reprogramming in Hepatocellular Carcinoma
Article Publication Date
26-Jun-2026