Open Access

REVIEW

Novel Strategies against Hepatocellular Carcinoma through Lipid Metabolism

Yuanyuan Yang^1,2,#, Peipei Zhao^1,2,#, Hepu Chen^1,3, Yixuan Tu⁴, Yujia Zhou², Xu Liu³, Lyly Sreang³, Zhigang Zhou^3,5,*, Jian Tu^1,2,*

1 Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, China
2 College of Pharmacy, Guilin Medical University, Guilin, 541199, China
3 Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, 541199, China
4 Department of Rheumatology and Immunology, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
5 Department of Anesthesiology, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, China

* Corresponding Authors: Zhigang Zhou. Email: ; Jian Tu. Email:
# These authors contributed equally to this work and shared the first authorship

(This article belongs to the Special Issue: Novel Biomarkers and Treatment Strategies in Solid Tumor Diagnosis, Progression, and Prognosis)

Oncology Research 2025, 33(11), 3247-3268. https://doi.org/10.32604/or.2025.066440

Received 08 April 2025; Accepted 15 August 2025; Issue published 22 October 2025

Abstract

Hepatocellular carcinoma (HCC) is characterized by its highly invasive and metastatic potential, as well as a propensity for recurrence, contributing to treatment failure and increased mortality. Under physiological conditions, the liver maintains a balance in lipid biosynthesis, degradation, storage, and transport. HCC exhibits dysregulated lipid metabolism, driving tumor progression and therapeutic resistance. This review aims to elucidate the roles of fatty acid, sphingolipid, and cholesterol metabolism in HCC pathogenesis and explore emerging therapeutic strategies targeting these pathways. Key findings demonstrate that upregulated enzymes like fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), enhance de novo lipogenesis and β-oxidation, and promote HCC proliferation, invasion, and apoptosis evasion. Sphingolipids exert dual functions: ceramides suppress tumors, while sphingosine-1-phosphate (S1P) drives oncogenic signaling. Aberrant cholesterol metabolism, mediated by HMG-CoA reductase (HMGCR), liver X receptor α (LXRα), and sterol regulatory element-binding protein 1 (SREBP1), contributes to immunosuppression and drug resistance. Notably, inducing ferroptosis by disrupting lipid homeostasis represents a promising approach. Pharmacological inhibition of key nodes—such as FASN (Orlistat, TVB-3664), sphingomyelin synthase (D609), or cholesterol synthesis (statins, Genkwadaphnin)—synergizes with sorafenib/lenvatinib and overcomes resistance. We conclude that targeting lipid metabolic reprogramming, alone or combined with conventional therapies, offers significant potential for novel HCC treatment strategies. Future efforts should focus on overcoming metabolic plasticity and optimizing combinatorial regimens.

---

Keywords

---