Advances in Lipid Metabolism Reprogramming in Hepatocellular Carcinoma (IMAGE)
Caption
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.
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Acknowledgement
Figures were created with BioRender (https://www.biorender.com/).
Funding
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).
Credit
Sulai Liu, Yu Peng
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CC BY-NC