Abstract
Purpose: Hepatocellular carcinoma (HCC) is the most common primary liver cancer, accounting for nearly 90% of cases and causing over 700,000 deaths annually. Increasing evidence indicates that dysregulated lipid metabolism plays a critical role in hepatocarcinogenesis by promoting tumor initiation, progression, metastasis, and drug resistance. This review provides a comprehensive overview of the molecular mechanisms underlying lipid metabolic reprogramming in HCC, highlights key therapeutic targets, and discusses emerging inhibitors with potential for future drug development.
Methods: A comprehensive literature search was conducted by critically reviewing published research articles, review papers, and clinical studies on lipid metabolism in liver cancer. Current advances were systematically evaluated, focusing on lipid metabolic pathways, associated molecular targets and signaling mechanisms, as well as small-molecule inhibitors, natural products, and clinically relevant therapeutic agents.
Results: Dysregulated lipid metabolism is a hallmark of HCC, contributing to cancer cell proliferation, survival, angiogenesis, metastasis, immune evasion, and resistance to conventional therapies. Alterations in de novo lipogenesis, fatty acid uptake, fatty acid oxidation, cholesterol biosynthesis, and phospholipid metabolism are frequently observed in HCC. Key enzymes and regulatory proteins, including fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), stearoyl-CoA desaturase-1 (SCD1), ATP citrate lyase (ACLY), sterol regulatory element-binding proteins (SREBPs), and peroxisome proliferator-activated receptors (PPARs), have emerged as promising therapeutic targets. Numerous synthetic compounds, natural products, and investigational inhibitors targeting these regulators have demonstrated encouraging preclinical and clinical potential for suppressing HCC progression.
Conclusion: Targeting aberrant lipid metabolism represents a promising therapeutic strategy for HCC. Improved understanding of lipid metabolic reprogramming and its regulatory networks has enabled the identification of novel molecular targets and therapeutic inhibitors. Future studies integrating lipid metabolism with precision medicine may accelerate the development of effective targeted therapies, facilitate early intervention, and improve clinical outcomes in patients with liver cancer.